T helper type 1 (Th1):
It induce cellular cytotoxicity and can activate the macrophage. It eradicate intra-cellular organism and stimulate cytotoxic T-cell maturation.
T helper type 2 (Th2):
It is importance in the immune response against parasitic infestation .It have a role in the development of allergy .
·T helper type 9 (Th9):
They are thought to have a role in the immune response against tumour cells, allergy, and autoimmune disease
T helper type 17 (Th17):
It is responsible for immune response against extracellular pathogens like bacteria and fungi. It have a role in chronic inflammatory responses in chronic infection, allergy, and autoimmunity.
T follicular helper (Tfh):
It is found to have a role in activating B lymphocytes and antibody production.
T regulatory (Treg):
It is responsible for developing and maintaining peripheral tolerance by negative feedback suppression of the immune response.
T cells CD4+ are differentiated in subtypes.
Th1cels act through cytotoxicity and macrophage activation ,thus having intracellular antimicrobial effect
Th2 cells have anthelmintic action and a role in asthma and allergy.
Th9 cells have antitumor action and have role in allergy and autoimmune disease.
Th17could have action against extracellular pathogens and role in chronic inflammation and autoimmunity.
Th follicular activating B lymphocytes and antibody production.
T reg essential for peripheral tolerance through suppression of immune response.
iTeg induced following antigen priming with TGFB.
Th3 have role in mucosal tolerance and development and /or maintenance of iT reg cells.
REFERENCES:
Heimall ,J: The adaptive cellular immune response : T cells and cytokines,Uptodate,Nov,2021.
Mohamed Essmat
3 years ago
Activated CD4 T lymphocytes can differentiate into several distinct subtypes: * T helper type 1: Stimulate cellular cytotoxicity and macrophage activation. Thus, it plays an essential role in elimination of intra-cellular organisms. *T helper type 2: They may have a role in the development of allergy and immune response against parasitic infestations. *T helper type 9: They have a role in the immune response against tumor cells, allergy, and autoimmune disease *T helper type 17: It is believed to play a role in the immune response against extracellular pathogens like bacteria and fungi. *T follicular helper: It is believed to have a role in activating B lymphocytes and increased antibody production. *T regulatory: Vital in developing and maintaining peripheral tolerance by negative feedback suppression of the immune response.
AMAL Anan
3 years ago
Role of T helper in graft damage with acute cellular and antibodies mediated Rejection.
CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment.
*** Lymphopoiesis:
T cells precursors originating from a common lymphoid hematopoietic stem cell leave the bone marrow to reach the thymus for maturation. Initially thought to be an evolutionary remnant with negligible function, the thymus is in fact a primary lymphoid organ indispensable for T-lymphocyte development.
**CD4+T Cells Activation and Differentiation:
The initial step of differentiation of the naïve cells is the antigenic stimulation as a result of interaction of TCR and CD4 as co-receptor with antigen-MHC II complex, presented by professional antigen presenting cells (APCs). TCR coupled with CD3 activation consequently induces a network of downstream signaling pathways, that eventually lead to naïve cell proliferation and differentiation into specific effector cells.
**Th1 Differentiation:
Interleukin 12 (IL12) and interferon γ (IFNγ) are the critical cytokines initiating the downstream signaling cascade to develop Th1 cells . IL12 is secreted in large amounts by APCs after their activation through the pattern recognition receptors .The IL12, in turn, induces natural killer cells(NK) to produce IFNγ.
***Th2 Differentiation
IL4 and IL2 are critical for Th2 differentiation. The major transcription factor involved in Th2 lineage differentiation includes the IL4-induced STAT6, which upregulates the expression of the master regulator GATA3 (GATA-binding protein) .3 distinct mechanisms of GATA3 involvement in Th2 differentiation have been postulated, including enhanced Th2 cytokine production, selective proliferation of Th2 cells through recruitment of Gfi-1, and inhibition of Th1 differentiation presumably by interacting with T-bet.
**Th9 Cells:
Initially characterized as a subset of Th2 cells, ongoing researches tend to classify IL9 secreting-Th9 cells as a distinct subset of CD4+ T cells.
***Th17 Cells Differentiation:
IL6, IL21, IL23, and TGF-β are the major signaling cytokines involved in Th17 cells differentiation, and retinoic acid receptor-related orphan receptor gamma-T (RORγt) is the master regulator.
***Regulatory Cells Differentiation:
iTreg cells are FOXP3+CD4+CD25+ cells, which are developed in the peripheral lymphoid organs after antigen priming, in contrast to the natural Treg (nTreg) which are released from the thymus as a distinct lineage with FOXP3 already expressed
***Follicular Helper (Tfh) T Cells:
Tfh are C-X-C motif receptor-5 (CXCR 5+) expressing cells and are located in follicular areas of lymphoid tissue, where they participate in the development of antigen-specific B-cell immunity .IL6 and IL21 are the main cytokines involved in the differentiation process .STAT3, activated downstream to cytokine signaling, is an important transcription factor of Tfh. However, unlike in Th17 development, TGFβ does not participate, and RORγt is not induced. In vitro, IL21 in the absence of TGFβ resulted in Tfh differentiation.
*** Plasticity of CD4+ Cells:
Unlike Th1 and Th2 cells, which are considered to be terminally differentiated, Th17 and Treg have shown plasticity, thereby suggesting that they are not terminally differentiated.
~Effector Functions>>>
***Th1 Cells:
Th1 cells are involved with the elimination of intracellular pathogens and are associated with organ-specific autoimmunity [114]. They mainly secrete IFNγ, lymphotoxin α (Lfα), and IL2. IFNγ is essential for the activation of mononuclear phagocytes, including macrophages, microglial cells, thereby resulting in enhanced phagocytic activity .
*** Th2 Cells:
Th2 cells mount immune response to extracellular parasites, including helminthes, and play major role in induction and persistence of asthma as well as other allergic diseases . The key effector-cytokines include IL4, IL5, IL9, IL13, IL10, IL25, and amphiregulin. IL4 is a major cytokine involved in allergic inflammation. It is involved in IgE switching and secretion by B cells.
*** Th17 Cells:
Th17 is responsible to mount immune response against extracellular bacteria and fungi. They are also involved in the generation of autoimmune diseases .The key effector cytokines include IL17A, IL17F, IL21, and IL22. IL17A and IL17F signaling occurs through a common receptor, IL17RA, thereby suggesting similar functions.
*** Regulatory CD4+T Cells:
Treg exists as natural thymus-derived subset with expressed FOXP3, and as peripheral-induced Treg cells, which arise from naïve CD4+CD25-cells after antigen priming in a relevant cytokine milieu .Treg and Tr1 play important role in the maintenance of immunologic tolerance to self and foreign antigen.
***Follicular Helper (Tfh) T Cells:
After TCR interaction and subsequent differentiation from the CXCR5−CCR7+CD4+ naïve cells, these CXCR5+CD4+T (Tfh) cells play significant role in mediating humoral immunity through interaction with B-lymphocytes. After having lost CCR7, the differentiated CXCR5+CCR7-pMHCII-specific Tfh cells enter the pregerminal centre for initial interaction with antigen-primed B cell,
References:
1. Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nature Reviews Immunology.
2. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R. Thymic generation and regeneration. Immunological Reviews. 2003;195:28–50.
3. Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature Reviews Immunology. 2006;6(2):127.
4. Daniels MA, Teixeiro E, Gill J, et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature. 2006;444(7120):724–729.
5. Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors. Annual Review of Immunology. 2006;24:419–466.
Ibrahim Omar
3 years ago
1- Graft damage with emphasis on acute cellular and antibody mediated rejection :
T helper cells are a subgroup of T- lymphocytes characterised by CD+4 cell surface markers. they are activated by antigens presented on APC. they will do activation and control of the whole immune responce involved in acute cellular rejection.
they differentiate into 4 major helper subpopulations (Th1, Th2, Th17, TFH) and one regulatory subpopulation (Treg).
Th1 lymphocytes : are the prototypical lymphocyte subpopulation responsible for rejection. Their differentiation is driven by IL-2and interferon-gamma. IL-12 is produced by activated DCs whereas IFN gamma is secreted by the Th1 lymphocytes themselves as well as other cells such as B lymphocytes. The transcription factors STAT1 & T-betare necessary for Th1 differentiation. Th1 lymphocytes produce copious amounts of IFN gamma , tumor necrosis factor-alpha (TNFa) and lymphotoxin (LT), which promote allograft rejection by activating macrophages, directly inflicting damage on graft endothelial cells, inducing production of complement-fixing IgG antibodies by B lymphocytes, and stimulating the differentiation of CD8+ T lymphocytes to CTL.
Th2 lymphocytes : They contribute to allograft rejection by production of IL-4, IL-5, IL-9, IL-10, and IL-13, which activate eosinophils, basophils, and mast cells and enhancing production of particular antibody isotypes, usually those that don’t fix complement. IL-10 also has immunoregulatory properties that dampen rejection.
T-h17 lymphocytes : They contribute to allograft rejection by promoting inflammation. Their differentiation is dependent on TGFb, IL-6, IL-21and on the transcription factors STAT6 AND RORgT. they promote inflammation by secreting IL-17, which stimulates the production of neutrophil chemoattractants by epithelial and other stromal cells in the graft.
TFH (follicular helper) lymphocytes : Theyplay a key role in antibody productionby providing help to B lymphocytes. Their generation is dependent on IL-21and on the transcription factor Bcl6. They express the chemokine receptor CXCR5, which guides their migration to B-cell follicles in secondary lymphocyte tissues. There they induce the differentiation of activated B lymphocytes to antibody-producing plasma cells via CD40L-CD40 interactions and the secretion of cytokines, namely IL-4 and IL-21.
2- Induction of tolerance :
T helper cells have a significant role in development of tolerance by contribution of their regulatory subtype,Treg. they express high levels of CD25 and the transcription factor Foxp3. the development of tolerance is poorly understood. however, one of the postulated mechanisms is that repeated antigenic stimulation induces the expression of inhibitory molecules that keep T cells hypo- or unresponsive.
Mohammed Sobair
3 years ago
Allograft rejection is primarily driven by the ability of host T cells to recognize
polymorphisms encoded within the MHC as well as multiple minor histocompatibility loci.
While all components of the innate and adaptive immune systems participate in graft
rejection, T lymphocytes and particularly CD4 T cells play important role in this process
In this process.
Rejection reaction consists of the sensitization stage and the effector stage. Sensitization stage: In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the
alloantigen expressed on the cells of the foreign graft. Two signals are needed for recognition of an antigen; the first is provided by the
interaction of the T cell receptor with the antigen presented by MHC molecules, the
second by a costimulatory receptor/ligand interaction on the T cell/APC surface.
Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface
with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86,
respectively), has been studied the most.
In addition, cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these
ligands and provides an inhibitory signal.
Other costimulatory molecules include the CD40 and its ligand CD40L (CD154). Effector stage: Alloantigen-dependent and independent factors contribute to the effector mechanisms.
Initially, ischemia induce a nonspecific inflammatory response.
Because of this, antigen presentation to T cells is increased as the expression of
adhesion molecules, class II MHC, chemokines, and cytokines is upregulated.
It also promotes the shedding of intact, soluble MHC molecules that may activate the
indirect allorecognition pathway. After activation, CD4-positive T cells initiate
cells for antibody production. Host T cells can be activated in response to an allogeneic stimulus by one of two
separate mechanisms:
Direct allorecognition:
It’s the response of host T cells recognizing intact donor MHC molecules present on the
surface of donor-derived antigen-presenting cells (APCs).
Indirect pathway:
Host T cells respond to processed donor-derived peptides bound to syngeneic MHC
molecules and presented in a self-restricted manner.
During acute rejection:
Donor-derived APCs, primarily dendritic cells, are present in grafted tissues as
passenger leucocytes that migrate post-transplant to host lymphoid tissues where they
directly stimulate host T cells. Dendritic cells are extremely powerful activators of naive
T cells, and this, coupled with the very large frequency of cells exhibiting direct
alloreactivity, has led to the concept that the direct pathway of allorecognition is
dominant way in acute rejection.
Chronic rejection:
The indirect pathway predominate in the later stages of the allograft response.
Evidence in favor of this includes the findings of large numbers of indirectly reactive T
cells (by limiting dilution analysis) in patients undergoing chronic rejection.
Direct alloreactivity may not necessarily be limited to the early phases, Donor endothelial
cells, expressing many of the same costimulatory and adhesion molecules found on
dendritic cells, are able to directly activate recipient CD8 T cells.
Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early
after transplantation, endothelial cells activated by T cell–derived cytokines and
macrophages express class II MHC, adhesion molecules, and costimulatory molecules.
These can present antigen and thereby recruit more T cells, amplifying the rejection
process.
Apoptosis:
The final common pathway for the cytolytic processes is triggering of apoptosis in the
target cell. Tolerance: Central (Intrathymic) Mechanisms of Tolerance: The chief mechanism of T-cell tolerance is the deletion of autoreactive T cells in the
thymus so that the organism is rendered self-tolerant. Peripheral (Nonthymic) Mechanisms of Tolerance:
many antigens are absent intrathymically or present at insufficient levels to induce
2- Prashant Malhotra, FIDSA; Ron Shapiro et al. Immunology of Transplant Rejection,
Medscape, Oct 16, 2019.
Ahmed mehlis
3 years ago
Helper T cells are the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells.
Helper T cells themselves, however, can only function when activated to become effector cells. They are activated on the surface of antigen-presenting cells, which mature during the innate immune responses triggered by an infection. The innate responses also dictate what kind of effector cell a helper T cell will develop into and thereby determine the nature of the adaptive immune response elicited.
the T cell can differentiate into either a TH1 or TH2 effector helper cell. These two types of functionally distinct subclasses of effector helper T cells can be distinguished by the cytokines they secrete. If the cell differentiates into a TH1 cell, it will secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and will activate macrophages to kill microbes located within the macrophages’ phagosomes. It will also activate cytotoxic T cells to kill infected cells. Although, in these ways, TH1 cells mainly defend an animal against intracellular pathogens, they may also stimulate B cells to secrete specific subclasses of IgG antibodies that can coat extracellular microbes and activate complement.
●Naïve T cells require at least two signals for activation. Both are provided by an antigen-presenting cell, which is usually a dendritic cell: signal 1 is provided by MHC-peptide complexes binding to T cell receptors, while signal 2 is mainly provided by B7 costimulatory proteins binding to CD28 on the T cell surface. If the T cell receives only signal 1, it is usually deleted or inactivated. When helper T cells are initially activated on a dendritic cell, they can differentiate into either TH1 or TH2 effector cells, depending on the cytokines in their environment: TH1 cells activate macrophages, cytotoxic T cells, and B cells, while TH2 cells mainly activate B cells. In both cases, the effector helper T cells recognize the same complex of foreign peptide and class II MHC protein on the target cell surface as they initially recognized on the dendritic cell that activated them. They activate their target cells by a combination of membrane-bound and secreted signal proteins. The membrane-bound signal is CD40 ligand. Like T cells, B cells require two simultaneous signals for activation. Antigen binding to the B cell antigen receptors provides signal 1, while effector helper T cells provide signal 2 in the form of CD40 ligand and various cytokines.
Most of the proteins involved in cell-cell recognition and antigen recognition in the immune system, including antibodies, T cell receptors, and MHC proteins, as well as the various co-receptors discussed in this chapter, belong to the ancient Ig superfamily. This superfamily is thought to have evolved from a primordial gene encoding a single Ig-like domain.
• CD4+ T cells are important to allograft destruction
Th1
• induces cell mediated immunity – producing IFN-g and IL-2 which stimulate activation of CD8+ cytotoxicity, macrophages -dependant delayed type hypersensitivity and the production of IgG2a by B cells,thus initiates complement which associated with allograft rejection
• may express FasL, enable them to exhibit cytotoxic activity
Th2
• Humoral immunity is driven by Th2 cells
• The type of T helper cell response is determined by the microenvironment in which APC and T cell interactions take place
• Secrete IL-4,IL-5,IL-9,IL-10 and IL-13- activate B cells and eosinophils to promote graft rejection
Th17
• produces IL-17,IL-21 and IL-22 which act alone and synergistically have shown to have impact in allograft rejection altering the Th1/Th2 paradigm
CD4+ T cell in regulation and transplant tolerance
CD4+CD25hiFoxP3+ Tregs( nTreg)
• express high levels of CD25 ( IL-2 receptor alpha chain) on the surface,thus provide a marker for isolation and characterisation
Adaptive ( induced) Tregs
• generated in the periphery by induction of FoxP3 expression in CD4+CD25- or CD4+CD25+ FoxP3-T cells
• Tr1 equipped a FoxP3- independent paracrine suppression mechanism regulated by the inhibitory cytokines IL-10 and TGF-beta to initiate immunoregulatory functions
References
Issa, F., Schiopu, A. and Wood, K., 2010. Role of T cells in graft rejection and transplantation tolerance. Expert Review of Clinical Immunology, 6(1), pp.155-169.
Ben Lomatayo
3 years ago
CD4 is important component of T lymphocytes with several effector cells which includes ;
TH1 cells ; activate Macrophages , provide help to B cells, and synthesised several important cytokines
TH2 cells ; mainly provide help to B cells including immunoglobulin class switching
TH17 cells ; are involved in inflammatory responses eg against bacteria
TFH cells ;help B cells
FOXP3 regulatory T cells ; suppresses T cell responses
TH 9 cells ; produces IL 9
Memory T cells ; important component of the immunologic memory, they have ability to response promptly and intensely upon re-exposure to the same antigen
FOXP3 regulatory T cells (piTreg) ; induces tolerance through the process of ;
Deletion and Apoptosis ; Activation – Induced Cell Death(AICD) : Mediated by interaction of Fas(CD95) with its ligand Fas-L on T ells
Anergy ; hypo-responsiveness of T or B cells to further antigenic stimulation. Common example is antigenic stimulation in absence of co-stimulation.
Regulation or suppression ; ; T reg control the type andmagnitude of a given immune response to foreign antigen, ensuring that the host remain undamaged
References ;
Oxford handbook of Nephrology & Hypertension, second edition
Egerton M et al.(1990) kinetics of mature T cell development in the thymus. Pro Natl Acad Sci 87: 2579-82
Russell DM et al.(1991) peripheral deletion of self-reactive B cells.Nature 354: 308-311
Dalia Ali
3 years ago
the exogenous antigen is presented on class II molecules—which are then recognized by CD4+ (i.e., expressing CD4 antigen) T helper cells. Activated T helper cells produce cytokines, which promote T-cell proliferation and differentiation, induce antibody secretion by B cells, and induce cytotoxicity in macrophages, natural killer cells, and cytotoxic T cells. Antigen specifi city is provided by clonally restricted T-cell receptors (TCRs) which recognize a peptide-HLA complex.
CD4 acts as a co-receptor, bringing the required proteins for activation into proximity of the TCR complex. Stimulation of the TCR results in phosphorylation of many proteins and activation of second messenger systems. This, together with a rise in intracellular calcium, activates the DNA-binding factors needed for IL-2 transcription and activates calcineurin—which through the modifi cation of the nuclear factor of activated T cells results in the formation of the functional protein that promotes IL-2 gene transcription. For complete recognition and response to alloantigen, at least two signals are required.
The most studied and potent costimulatory pathway is the CD28-B7 ligand receptor binding. Without stimulation of both signals, there is immune anergy.
The local cytokine milieu and the antigen presented result in the differentiation of naive T helper cells into Th1 or Th2 cell subsets, which secrete different cytokines and hence have different functions.
Th1 cells are mainly involved in
cell-mediated immunity, whereas Th2 cells are involved in humoral immunity. The recruitment, proliferation, and differentiation of leukocytes in rejection are all dependent on cytokine and chemokine production. Chemokines also facilitate adhesion of the leukocytes to the endothelial wall prior to diapedesis into the tissue, either directly or by activating integrins or adhesion molecules.
Antibody-Mediated Rejection
Acute humoral rejection, beyond the immediate reperfusion period, can be diffi cult to diagnose because it may manifest as acute tubular injury with no evidence of circulating antibodies. This is not to say that antibodies are not present but rather that the currently available techniques are not sensitive enough to detect them. Other suggested explanations for the lack of detectable antibodies include that the graft absorbs the antibodies (removing them from the plasma) and that the rejection is caused by factors other than antibodies, such as platelet activation.
B-cell activation and regulation occur via several mechanisms that are T-cell dependent or independent. B-cell responses against MHC antigens are T-cell dependent and require the involvement of antigen-presenting cells and costimulatory molecules such as CD40 ligand or soluble interleukins. These responses take two to three weeks to develop and lead to immunologic memory, allowing a more effi cient antibody response upon repeat stimulation.
Denis F. COMPREHENSIVE PEDIATRIC NEPHROLOGY. ISBN: 978-0-323-04883-5.2008
Nasrin Esfandiar
3 years ago
· CD4+ T cells are one of the most important components of rejection process .They include Th1, Th2 and recently recognized Th-17. Treg, Tfh and TH9 are other subsets with different functions.
· Th1 cells secret IFN-γ and IL-2 that have different function in activation of CD8+Tcells, macrophages and B cells and then complement system. They express Fas ligand and cytotoxic activities.
· On contrary IFN- γ can induce T regs and inhibit Th 17 cells.
· Th2 cells secret different interleukins (4, 5, 9, 10 and 13) which can activate B cells and induce eosinophil infiltration .They have a special factor named GATA-3. IL-9 is active in allergy and its role in rejection should be determined.
· Th17can recruit neutrophils to graft by secreting IL-17, IL21 and IL-22, IL-17 is more important in acute rejection than chronic form.
· Cytokines induce transition of T lymphocytes to memory Tcells (TM)
· Tregs or regulatory Tcells are important to induce tolerance by expression of CD25 or secretion of IL-10 and TGF β. Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol. 2010 Jan;6(1):155-69.
Asmaa Khudhur
3 years ago
naive CD4 T cell needs Ag recognition to be activated by direct and indirect bath ways .
After CD4 T cell recognition, 3 signals leads to its activation:
Signal 1/ TCR CD4 and Ag on ApC
Signal 2/CD80/86 on APC and CD23 on T cell
Signal 3/CD4Tcellproliferation and differentiation into effector cells which include:
Th1 secret inflammatory cytokines and aggravate immune system.
Th2 secret inflammatory cytokines and inhibit immune system
Th17 aggravate immune system
Tfh start humoral immune response
T memory it’s life long resistant to treatment.
It induce tolerance by the aid of Treg.
fakhriya Alalawi
3 years ago
The ability of recipient T cells to recognize donor-derived antigens, called allorecognition, initiates allograft rejection. Once recipient T cells become activated, they undergo clonal expansion, differentiate into effector cells, and migrate into the graft where they promote tissue destruction. In addition, CD4 T cells help B cells produce alloantibodies. The Naïve CD4+ T helper cells (nTh) are one of the first immune cells to be activated post-transplant, playing a key role in the rejection. Activated nTh develop into either Th1 (pro-inflammatory) or Th2 (anti-inflammatory) subtypes. Each subtype orchestrates a characteristic, immune response profile.
In the presence of TGF-β and IL-6, nTh differentiate into Th17 cells, a novel subset of Th cells that secrete IL-17 whose role in transplant immunology is still unclear. However, it appears that Th17 cells together with Th1 and Th2 cells play an important role in mediating allograft rejection. A Th1 response is correlated with acute rejection episodes with the production of pro-inflammatory cytokines – IFNγ, IL-2, IL-12, TNFα and GM-CSF. This cytokine profile activates macrophages, natural killer (NK) cells and cytotoxic T cells (Tc) which are drawn to the graft and activate caspases that induce cell apoptosis.
Memory CD4+ T cells not only become effector cells upon reactivation but also provide help for the robust activation of donor-reactive effector CD8+ T cells. These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival. Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft. Once in the graft parenchyma, these memory CD8+ T cells proliferate extensively, upregulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
Influence of Memory T Cells on Allograft ToleranceEven though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances, they demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses. Krupnick et al. have reported that early infiltration of central memory CD8+ T cells is essential for lung allograft acceptance after treatment with CTLA4-Ig and anti-CD154 mAbs. Similarly, CD8+CD45RClo cells with regulatory properties have been described in rat models of solid organ transplantation and GVHD.
References:
1. Liu Z, Fan H, Jiang S. CD4(+) T-cell subsets in transplantation. Immunol Rev. 2013 Mar;252(1):183-91.
2. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010 Jan;25(1):61-74.
3. Benichou G, Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology. 2017 Feb 28;8:170.
Ramy Elshahat
3 years ago
What is the role of T helper cells (CD4) in
Graft damage with emphasis on acute cellular and antibody mediated rejection.
There is two main types of Tcells Cd4(helper) which interact with antigen presented by APC on HLA class 2
Cd8(cytotoxic) which interact with antigen presented on HLA class 1
Naive Cd4Tcell needs antigen recognition to be activated (adaptive) by 3 main pathways
Direct: by donor APC (100folds potent)
indirect:by antigenic part presented by recipient APC
Semidirect: by whole donor HLA presented by recipient APC
After Cd4Tcell recognition it’s activation started by 3signals
Signal 1: connection between TCR Cd4 and antigen presented on APC
signal 2: connection between cd80/86 on APC and Cd28 on t cell
Signal 3: Cd4Tcell proliferation under effect of IL 2on Cd25 and differentiate into effector t cells which includes
Th1: secrets IL2 and interferone gamma and other inflammatory cytokines and aggravated immune system
Th2: secrets IL10 and antiinflammatories cytokines and inhibit immune response
Th17: secrets IL17 and aggravates immune response
Tfh: which introduce antigen to bcell in the 2ry lymphoid organs and starts humoral immune response
Tmemory: which life longer and get activated without signal 2 and resistant to treatment.
What is the role of T helper cells (CD4)in Induction of tolerance
One of the effector Cd4Tcell is T-regulatory
Treg: which also includes subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy
Its stimulate tolerance by 2main mechanisms
1) contact dependent:it express cd25 on its surface and interact with conventional t cell on signal 2 stimulation and induce anergy
2)non contact dependent: it secrets IL10 and TGF beta which influence inhibitory effect on adaptive immune system.
Also treg affected by immunosuppressant medications as below
Cni decrease number and function of Treg by inhibition of IL2 secretion
ATG depleting both conventional and treg but treg regenerate faster
Alemutzumab affect conventional tcell more than treg and elicit more tolerance.
MTOR,MMF and steroids increase treg expression and activity.
Reference:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169
2) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336
Tahani Hadi
3 years ago
After activation of T lymphocytes by cytokines that produced by APCs it will be proliferate and differentiate into 4 major helper cells (Th1,Th2,Th17,Tfh)and one regulatory subgroup, CD+ T cells can be cytotoxic.
Th1 lymphocyte: this type is responsible for graft rejection by producing cytokines leading to macrophages activation and depend on IL-2 and interferon gamma for their proliferation.
Th2 lymphocytes :IL4 and transcription factors STAT6 and GATA3 are responsible for their differentiation ,they are responsible on allergic reaction also activation of eosinophils, basophils and mast cells ,Th2 lymphocytes inhibit Th1 lymphocyte in delay rejection .
Th17 lymphocytes: produced by IL-6 and transforming growth factor B ,and they are developed in early stage of immune reaction also cause inflammatory response to bacterial infection, they have ability to produce IL-17
Tfh lymphocytes : their proliferation depen on IL-21 and on the transcription factor Bc16 ,they play role in differentiation of activated B cells to Ab producing plasma cells also they contribute in alloantibodies production that affect on graft survival.
Mujtaba Zuhair
3 years ago
THE helper T lymphocyte orchestrates the adaptive immune system . These cells can secret cytokines and activates B cells to become plasma cells . Many subtypes of T helper lymphocytes:
TH1 Lymphocytes : secrets interferon and TNFa which can lead to graft damage directly, also it activate macrophages, stimulate Cytotoxic T lymphocytes, stimulate the differentiation of B cells into immunoglobulin producing plasma cells.
TH2 Lymphocytes : secret cytokines Iike IL4, IL5 , IL10 which activates mast cells and basophiles . TH2 can suppress TH1 lymphocytes.
TH17 Lymphocytes : secretes IL17, which leads to attraction of inflammatory cells to the graft.
Tfh Lymphocytes: T follicular helper lymphocytes stimulate B cell to differentiate to plasma cells through CD40- CD40L and produce IL4, IL21.
Once helper T cells activated By direct or indirect pathway , they start to proliferate and migrate to the graft and secrete cytokins that activate cytotoxic T cells and NK cells and macrophages also secrete interferon that leads to graft damage and cellular mediated rejection.
T regulatory Lymphocytes (Fox3 +): These cells can suppress T helper and T cytotoxic Lymphocytes and can induce tolerance to the graft .
Wessam Moustafa
3 years ago
CD4+ T helper cells are one of main cells playing a key role in rejection.
Activated CD4 T cells develop into either Th1 (pro-inflammatory) or Th2 (anti-inflammatory) subtypes.
Each subtype leads to a characteristic, immune response profile .
In the presence of certain cytokines
T helper cells differentiate into Th17 cells, a novel subset of Th cells that secrete IL-17 whose role in transplant immunology is still unclear.
*In case of cellular rejection, activation of t helper cells eventually causes production of pro-inflammatory cytokines – IFNγ, IL-2, IL-12, TNFα and GM-CSF.
This cytokine profile activates macrophages, natural killer (NK) cells and cytotoxic T cells (Tc) which are drawn to the graft causing its destruction
Th2 cells result in the activation of B cells.
B cells express MHC class II, which present to Th2 cells (indirect), resulting in Th2 activation/proliferation.
The resultant Th2 cells are specific for B cell and secrete IL-2 for B-cell proliferation and IL-4 and -5 for antibody class switching.
activated B cells differentiate into plasma cells which secrets antibodies (mainly IgG and IgM) with specificity towards the graft.
Interaction of Ab with the graft endothelium eventually leads to the activation of complement, and cell destruction
B cells develop into memory cells and developing an immunological memory towards the graft.
T regs which is a subset of t helper cells ,inhibits deleterious immune response of T helper cells on self antigens thus promoting tolerance to transplanted organ.
An important discovery in the field of Treg therapy in humans is the finding that Tregs can be isolated and expanded in vitro while maintaining immunoregulatory function.
Studies showed that infusion of Tregs has the potential to induce long-term donor-specific tolerance without interfering with immune responses to pathogens and tumors in transplant patients.
Fatima AlTaher
3 years ago
T helper helper T cells are a CD4 cells that can differentiate into several different subtypes, including Th1, Th2, Th3, Th17, T reg and T f h . Each subtypes secretes a different panel of cytokines that can drive the immune response in a specific direction, so these CD4+T helper cells play a vital role in various immunologic processes as activation of cytotoxic T cells and APCs , maturation and differiation of B cells into plasma cells and memory B cells , antibody production by B cells, recruitment of various inflammatory cells PMNs, eosinophils and basophils as well as development of tolerance and suppression of immune responses
T lymphocyte recognize the non self HLA Ags on the transplanted graft , after their presentation on either donor APC (direct allorecognition pathway) or on recipient APCs after processing these Ags . This is followed by priming of both CD4+ and CD8+ T lymphocytes .The activated T helper cells stimulate differitaion of B lymphocytes into Ab producing plasma cells via IL 21 production which may induce graft injury , T helper cells are also important for the survival of memory B cells . In their study , de Graav, G and his collegues found increased number of follicular T helper cells in association with B cells infilterating the graft during rejection and the level of follicular t cells were positively correlated with pretransplantation DSA level which indicates the role of both B and T helper cells in graft rejection . (1) 1- de Graav, G. N., Dieterich, M., Hesselink, D. A., Boer, K., Clahsen-van Groningen, M. C., Kraaijeveld, R., Litjens, N. H., Bouamar, R., Vanderlocht, J., Tilanus, M., Houba, I., Boonstra, A., Roelen, D. L., Claas, F. H., Betjes, M. G., Weimar, W., & Baan, C. C. (2015). Follicular T helper cells and humora
MICHAEL Farag
3 years ago
The role of T helper cells (CD4) in the following?
Graft damage with emphasis on acute cellular and antibody mediated rejection
In cellular rejection
T cells cause allograft rejection either by eliciting a DTH (delayed-type hypersensitivity) response or through cytolytic/cytotoxic activity . DTH responses are primarily mediated by alloantigen-specific CD4+ Th1 cells, which secrete IFNg(gamma) and TNF-a(alpha). These
proinflammatory cytokines activate monocytes and macrophages which, in turn, cause nonspecific tissue injury through the release of proteolytic enzymes, nitric oxide, and other soluble factors. These factors affect vascular tone and permeability, in addition to promoting chemotaxis and further activation and differentiation of antigen-specific T cells
In antibody mediated rejection
T- helper is important for maturation of B- cells and enhancing its proliferation and production of antibodies
Induction of tolerance
In healthy individuals, immune homeostasis is maintained through a balance between effector and regulatory cells of either T or B cell lineage. Of these, CD4+CD25+FoxP3+ regulatory T
cells (Treg) have received the most attention as targets for inducing peripheral tolerance.
Treg in humans are CD4+ T lymphocytes that express high levels of CD25 and the transcription factor Foxp3. Anergy and exhaustion refer to the state in which T or B lymphocytes become unresponsive to re-stimulation with antigen. tolerant transplant patients show a suppressed DTH response to donor antigens
Nazik Mahmoud
3 years ago
CD4 had four major helper subpopulation:
1-Th1:produced by dentritic cells,they activate macrophages by produce lymphotxin,INF gama and TNF alfa which lead to damage of graft endothelial cells and stimulate CD8 T lymphocytes to CTL.
2-Th2: responsible for allergic reaction,activated by lL-4 lead to production of eosinophils,basophils and mast cells,it can lead also to antibody production.some times inhibit Th1 formation and delay rejection.
3-Th17: responsible for responding to fungal infections,contribute to allograft rejection by promoting inflammation,also can lead to formation of tertiary lymphoid tissue at the sites of chronic inflammation which share similar architecture to lymph nodes which observed in allograft with chronic rejection.
4-Tfh(follicular helper): help B lymphocytes to produce antibodies via CD40l -CD40 interaction, it is beneficial by blocking T-lymphocytes activation
Shereen Yousef
3 years ago
T-cell phenotypes
Activation of naive CD4+ T cells results in T-cell maturation and differentiation to phenotypes with effector functions.
CD4+ T helper lymphocytes play an essential role in adaptive immunity and in inducing immune response.
They are involved in both AMR and CMR.
CD4+ T cells can differentiate from pluripotent naive cells (Thp) into at least four types , Th1, Th2, Th17, and regulatory T cells (Treg) 1.
Th1 cells are the proinflammatory T cell, play central role in delayed-type hypersensitivity responses and the response to intracellular pathogens such as Mycobacteria sp. many studies of transplant rejection have concentrated predominantly on Th1 responses and IFN-γ production( which is also produced by other cells ) 2.
T-bet, the signature transcription facture of Th1 cells, can be identified in renal transplant biopsys during of acute rejection, similar to IFN-γ, T-bet is pleiotropic and also expressed by many other cell types including DCs and natural killer cells and therefore not specific to Th1 cells during rejection 3.
interferon gamma and IL-2 leading to CD8+ cytotoxicity, macrophage dependent delayed type hypersensitivity and IgG2 synthesis from B cells stimulating complement leading to rejection.These are mainly responsible for cell-mediated immunity.
Th17 cells produce the highly proinflammatory cytokine, IL-17, and are central to the response to extracellular pathogens.
Th17 is strongly association with autoimmune diseases and are now considered principal mediators of human autoimmune diseases 4.
In the transplant setting, an elevation in IL-17 mRNA in rejecting rat renal allografts and IL-17 protein in infiltrating mononuclear cells can be seen as early as day 2 after transplantation
IL-17 protein is elevated in human renal allografts during subclinical rejection, together with detectable IL-17 mRNA in urinary sediments 5.
Follicular T helper cells are CD127- , provide help for activated B lymphocytes leading to plasma cell derived antibodies.
Tregs
Tregs, specifically CD4+ T cells expressing high levels of CD25 (the IL-2 receptor α-chain) and the transcription factor (FOXP3),are derived by thymic selection of cells with higher affinity for self-MHC (natural or ‘n’Tregs) and also from the periphery during immune activation in the presence of TGF-β and/or retinoic acid (inducible or ‘i’Tregs).
Tregs have potent suppressive function and
important in maintenance of tolerance to self-antigens, preventing development of autoimmune diseases 6.
Tregs don’t have significan effect in the early posttransplantion period but greater impact on modifying chronic rejection. Indeed, emerging data show that Treg numbers present in human protocol renal transplant biopsies showing borderline or acute cellular rejection at 1 year correlate inversely with better creatinine and less interstitial inflammation.
the presence of high numbers of Tregs (measured using the surrogate marker of FOXP3/CD3 ratio) in renal biopsy specimens containing inflamed fibrosis correlates with better allograft survival 7.
Tregs may also have an impact on humoral alloresponses, which are of relevance in chronic rejection. a tolerizing protocol, involving pretransplant treatment of recipients with anti-CD4 monoclonal antibody plus donor-specific transfusion, resulted in the induction of CD4+ Treg cells, which prevented the generation of alloantibody and graft rejection.
Tolerance induction in this model was actively dependent on the continued presence of Tregs and could be reversed with depletion of these cells 8.
Two broad possibilities for Treg therapy exist in humans,one is by induction of Tregs from naive precursors in vivo using targeted delivery of alloantigen under tolerizing conditions and the other is by infusion of autologous Tregs expanded from peripheral blood ex vivo
1 McGeachy, D.J. Cua
Th17 cell differentiation: the long and winding roadImmunity, 28 (2008), pp. 445-453
2 Alcaide, T.G. Jones, G.M. Lord, et al.
Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue
J Exp Med, 204 (2007), pp. 431-439
3 Sawitzki, C.I. Kingsley, V. Oliveira, et al.
IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo
J Exp Med, 201 (2005), pp. 1925-1935.
4 Afzali, G. Lombardi, R.I. Lechler, G.M. Lord
The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease Clin Exp Immunol, 148 (2007), pp. 32-46.
5 Loong, H.G. Hsieh, W.Y. Lui, et al.
Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection
J Pathol, 197 (2002), pp. 322-332.
6 H.D. Ochs, E. Gambineri, T.R. Torgerson
IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity .9immunol Res, 38 (2007), pp. 112-121.
7 Taflin, D. Nochy, G. Hill, et al.
Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft functionTransplantation, 89 (2010), pp. 194-199.
8 C.J. Callaghan, F.J. Rouhani, M.C. Negus, et al.
Abrogation of antibody-mediated allograft rejection by regulatory CD4 T cells with indirect allospecificity
J Immunol, 178 (2007), pp. 2221-2228.
Esmat MD
3 years ago
CD4+ T lymphocyte differentiate into major helper subgroups with effector activities (Th1, Th2, Th9, Th17, Th22, and follicular helper T cells [Tfh]) and those with regulatory activities (natural regulatory T cell [nTreg], induced regulatory T cell [iTreg (type 1 regulatory T cell [Tr1])], Th3). CD4+ T lymphocytes can also be cytotoxic.
All effector T-lymphocyte subsets participate in allograft rejection, although some of them play a more dominant role than others.
Th1 lymphocytes are the prototype of lymphocytes responsible for rejection. Their differentiation is driven by IL-12 and INFγ. The transcription factors STAT1 and T-bet are necessary for their differentiation.Th1 lymphocytes produce large amounts of INFγ, TNFα and lymphotoxin which promote allograft rejection by activating macrophages, direct damage on graft endothelial cells, inducing production of complement-fixing IgG antibodies by B lymphocytes, and stimulating the differentiation of CD8+ T lymphocytes to CTL (cytotoxic T lymphocytes)
Th2 lymphocytes are the lymphocytic subset responsible for allergic reactions. They also contribute to allograft rejection. Their differentiation depends on IL-4 and transcription factors STAT6 and GATA3. They produce IL-4, IL-5, IL-9, IL-10, and IL-13, which activate eosinophils, basophils and mast cells and usually enhance the production of not complement fixing antibodies. IL-10 also has immunoregulatory properties that prevent rejection. The role of Th2 lymphocytes in mediating rejection is less potent than Th1 lymphocytes and may inhibit Th1 formation and delay rejection, so they have a dual role in kidney transplantation.
Differentiation to the Th17 phenotype depends on TGFβ, IL-6, and IL-21 and on the transcription factors STAT6 and RORγT.Th17 lymphocytes produce IL-17, and contribute to allograft rejection via inducing inflammation. IL-17 stimulates the production of neutrophil chemoattractants by epithelial and other stromal cells in the graft. Th17 lymphocytes also participate in the formation of tertiary lymphoid tissues at sites of chronic inflammation which have been observed in renal allografts undergoing chronic rejection that suggests their participation in the local immune response.
Th9 lymphocytes that produce IL-9, are involved in either immunity or tolerance.
Tfh (follicular helper lymphocytes) play a key role in high affinity antibody production by providing help to B lymphocytes. Their generation is dependent on IL-21 and on the transcription factor Bcl6. They induce the differentiation of activated B lymphocytes to antibody producing plasma cells. Engagement of CD4 on B lymphocytes by CD 154 on CD4+ T lymphocytes is an important mechanism by which CD4+ T lymphocytes provide help to B lymphocytes for IgG production.
Secretion of cytokines, namely IL-4 and IL-21, are essential for this differentiation as well. Thus, Tfh lymphocytes are important for driving the production of alloantibodies that are detrimental to graft survival. In the presence of appropriate cytokines and B cell interactions, Tfh cells can differentiate into Th1-like, Th2-like, or Th17-like Tfh cells.
Treg cells typically comprise 1 to 2 percent of the total CD4 population, but overall are critically responsible for the suppression of effector CD4 T cell effects through contact inhibition of activity between APC and effector T cells or direct cytotoxicity.
Amit Sharma
3 years ago
CD4+ T cells have an important role in alloresponse.
They are very much involved in graft damage by both cell-mediated immunity and antibody-mediated immunity.
The various subsets of CD4+ T cells include: (1)
1) Th1 cells: These secrete interferon gamma and IL-2 leading to CD8+ cytotoxicity, macrophage dependent delayed type hypersensitivity and IgG2 synthesis from B cells stimulating complement leading to rejection. They also have FasL which leads to cytotoxicity. These are mainly responsible for cell-mediated immunity.
2) Th2 cells: These have role in humoral immunity. They secrete IL 4,5,9,10 and 13, activating B cells and eosinophils leading to chronic graft rejection.
3) Th17 cells: these secrete IL17, 21 and 22 leading to recruitment of neutrophils at rejection site. These have role in acute rejection in early post transplant phase .
4) Tfh: Follicular T helper cells are CD127- , provide help for activated B lymphocytes leading to plasma cell derived antibodies.
5) Treg (regulatory T cells): These suppress potentially deleterious actions of the Th cells. (2) These have role in immune tolerance.
Reference:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169 2) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336.
Alyaa Ali
3 years ago
CD4+ cells are T-helper cells that have CD4 markers on their surface. CD4+ T helper lymphocytes play an essential role in adaptive immunity and play an important role in establishing and maximizing the immune response. These cells have no cytotoxic or phagocytic activity, and cannot kill infected cells or clear pathogens. However, they mediate the immune response by directing other cells to perform these tasks. Th cells are activated through TCR recognition of antigen bound to class II MHC molecules. once CD4+ T cell recognize foreign antigens on MHC class II , they become activated , Once T cell activation occurs, a chain of intracellular events is triggered under the influence of a variety of growth factors as IL-2 with expression of cell surface molecules and production of cytokines which lead to 1. stimulation of monocytes that play an important role in destruction of graft . 2 . stimulate the activation and proliferation of cytotoxic CD8 T cells and natural killer cells ( achieve cellular inflammatory responses) . 3 .stimulation of B cells with proliferation and differentiation into plasma cells . plasma cells release soluble immunoglobulins or antibodies which can bind allogeneic cells. Antibodies can cause cell damage by fixing of complement or by mediating antibody dependent cellular cytotoxicity (humoral immune response).
They are a special subpopulation of CD4 cells. Type 1 helper T cells (Th1) cells produce interleukin-2 (IL-2) and interferon-gamma (IFN-g) and induce macrophage activation, leading to delayed-type hypersensitivity responses. Acute allograft rejection is predominantly mediated by a Th1 immune response. Type 2 helper T cells (Th2) cells produce interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), and interleukin-13 (IL-13), and provide help for B-cell function . IL-4 is a growth factor for B cells and antibody production and also can directly inhibit T cell maturation into the Th1 pathway.This act against parasitic (predominantly helminthic) infections in mammals.A switch from a Th1 to a Th2 cytokine expression is associated with allograft tolerance . Type 17 helper T cells( Th17) cells are a T cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance. regulatory T (Treg) cells limit and suppress the immune system and, thereby, may function to control aberrant immune responses to self-antigens and the development of autoimmune disease. References Santarlasci V, Cosmi L, Maggi L, Liotta F and Annunziato F : IL-1 and T helper immune responses. Front. Immunol.2013: 4:182. Hand book of kidney transplantation by G.M.Danovitch,fifth edition. UpTo Date
Well done Alia you have a clear grasp of the helper Tcells, waiting for the Tregs.
Assafi Mohammed
3 years ago
T helper cells (CD4)
Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients.CD4 T cells recognize peptide/MHC class II complexes.MHC class II molecules are constitutively expressed on the surface of professional antigen presenting cells, but expression can be induced on many cell types with activation.
After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist.
After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA.In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures.
Some studies have implicated CD4 T cells as sufficient on their own to result in complete graft destruction {CD4+ but not CD8+ cells are essential for allorejection.Krieger NR, Yin DP, Fathman CGJ Exp Med. 1996 Nov 1; 184(5):2013-8.}, while other studies have suggested that CD8 T cell activation alone results in acute rejection
For the rejection of grafts mismatched for minor histocompatibility antigens, cooperation between CD4 and CD8 T cells is thought to be required for maximal graft rejection. CD4 T cells have been shown to facilitate CD8 T cell differentiation by direct cell-to-cell contact or by producing effector cytokines, such as IL-2 and IFN-γ, that directly support CD8 T cell differentiation and killing . Alternatively, it is possible that CD4 T cells act indirectly through a dendritic cell to be a more potent stimulator or suppressor of CD8 T cell responses . This indirect effect could be mediated through CD154 expression on CD4 T cells and CD40 expression on dendritic cells.
T helper cells (CD4) & induction of tolerance
CD4+ T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self-tolerance in CD4+ T cells.
Activation of CD4+ T cells is regulated by not only the binding of peptide-major histocompatibility complexes to T-cell receptor but also costimulatory signals from antigen-presenting cells.
Recently, there has been progress in understanding the extracellular and intracellular mechanisms that are required for implementation and maintenance of T-cell tolerance. Understanding of the molecular mechanisms underlying T-cell tolerance will lead to development of pharmacological approaches either to promote the tolerance state in terms of autoimmunity or to break tolerance in cancer.
T follicle helper cells (Tfh cells) are a specialized subset of CD4+ T cells. Yuhong et al reported a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. (Chen, Yuhong, et al. “CXCR5+ PD-1+ follicular helper CD8 T cells control B cell tolerance.” Nature communications 10.1 (2019): 1-15.) https://www.nature.com/articles/s41467-019-12446-5
Doaa Elwasly
3 years ago
Upon activation of naive CD4+helper T (Th) cells by antigen-presenting cells, it differentiate into different Th cell subsets, Th1, Th2and Th17, with different cytokines and effector functions This is promoted by the IFN-c-induced activation of STAT-1 and T-bet, the Th1specific transcription factor.T-bet promotes Th1 lineage and forms positive feedback loop with IFN-c.
On the other side IL-4 induces differentiation of Th2, engagement of IL-4 receptor leads to the phosphorylation of STAT-6which binds to the IL-4 promoter and inducesIL-4 production, thus forming a positive feedback
loop to increase Th2 differentiation.Several authors published that prevalence of Th1 over Th2 is specific to acute renal allograft rejection .
Th17expresses a transcription factor different from those of Th1 and Th2
cells, the retinoic acid-related orphan receptor ct (RORct) The combination of the IL-6with TGF-b induces the differentiation of Th17cells producing large quantities of IL-17. (1)
Antigens nature and graft type affects mechanisms of allograft rejection. T lymphocytes can injure allografts of dispersed cells by direct effector mechanisms also can act indirectly through secreted cytokines which can themselves directly injure target cells or through effects of cytokines on macrophages. Renal allograft can be rejected through effects on blood vessels rather than injury to the parenchymal cells (2)
CD4+ cells recognize class II MHC molecules on the donor tissue (HLA-DP, HLA-DQ, HLA-DR), and are induced to secrete interleukin-2 (IL-2), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), which activate CD8+ cells, NK cells, and macrophages. The Th1 CD4+ cells also give signals to activate the Th2 CD4+ group to secrete the cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-10 (IL-10), which can activate B cells and immunoglobulin production.(3)
Some T cells can be demonstrated to downregulate other T cell and/or B cell responses, referred to as T-suppressor cells,known as regulatory T cells (T-regs). There are two basic types of T-regs; tTregs that are produced in the thymus and are involved in controlling autoimmune disease; and iTregs that are induced during immune responses and are terminating immune responses .T-reg cells help maintain the balance between protection and an immune-mediated injury .(4)
Chimeric antigen receptor (CAR) T cell therapy in the induction of graft tolerance by immune cells been limited to the laboratory. Recently, innovative CAR-Treg therapies in animal transplant models was demonstrated CAR-Tregs genetically modified with coding CARs are non-MHC dependent and have better antigen specificity. The mechanism of CAR-Tregs targeting specific tissue sites and successfully reduced GVHD in the mouse model .The mAb-CAR-Tregs targeted MHC class I proteins on allografts and prolonged it’s survival .(5)
1-Loverre A etal.T helper 1, 2 and 17 cell subsets in renal transplant patients
with delayed graft function.Transplant International 2010 ,24 (2011) 233–242
Th1 favours rejection and graft damage ( it is pro inflammatory and secrete pro inflammatory cytokines), Th2 favours tolerance as it is antiinflammatory
I think all the Th-cells with subtypes that promote the expression or activiation of proinflammatory cytokines and chemtokines like Th1, Th2, Th9, Th17, Th22, Thf all can lead to rejectionand graft damage while the Th-cells with subtypes promote the immunesuppressive and immune modulation effect can help with tolerance induction like Treg , iTerg anf Th3 cells
Th1 subtype of naive CD4+ T cells is pro-inflammatory, while Th2 subtype is antiinflammatory. Hence Th1 has role in acute rejection and graft damage.
Th2 is antiinflammatory, hence has role in tolerance. But it also has role in chronic rejection by secretion of IL-4,5,9,10 and 13 activating B cells and eosinophils promoting chronic rejection.
Th1 is proinflammatory cells secrets INF gama, IL-2 which activate CD8 + cytotoxic cells macrophages, & production go IgG2 by Cells that activate complement lead graft rejection.
Th2: produce IL-4, IL-10 & Il-13, these cytokines will activate B cells & induce chronic rejection.
Although TH2 also may induce tolerance and have som anti-inflammatory action
Generally TH1 involved in rejection and graft damage, while TH2 may take part induction of tolerance. Interestingly TH2 may provide B cells help including immunoglobulin class switching.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
Traditionally, T cells were CD41 helper or CD81 cytotoxic T cells, and with antibodies, they were the soldiers of immunity. Now, many functionally distinct subsets of activated CD41 and CD81 T cells have been described, each with distinct cytokine and transcription factor expression.
1-CD41 T cells, these include Th1 cells expressing the transcription factor T-bet and cytokines IL-2, IFN-g, and TNF-b
2-Th2 cells expressing GATA-3 and the cytokines IL-4, IL-5, and IL-13
3-Th17 cells expressing RORgt and cytokines IL-17A, IL-17F, IL-21, and IL-22.
The cytokines produced determine the immune inflammation that they mediate
T regulatory cells or spies were characterized as CD81 T cells expressing I-J in the 1970s.
In the 1980s, suppressor cells fell into disrepute when the gene for I-J was not present in the mouse MHC I region. At that time, a CD41 T cell expressing CD25, the IL-2 receptor-a, was identified to transfer transplant tolerance. This was the same phenotype of activated CD41CD251 T cells that mediated rejection. Thus, the cells that could induce tolerance and undermine rejection had similar badges and uniforms as the cells effecting rejection.
Clin J Am Soc Nephrol 10: 2050–2064, 2015. doi: 10.2215/CJN.06620714
Ban Mezher
3 years ago
Th lymphocytes are the most important cells in adaptive immunity, as it is necessary for all adaptive immune responses.It activate B cells, macrophages & cytotoxic T cells. Naive T cells are activated through TCR when interact with MHCII in presence of co stimulatory molecules on APC.Th cells is the first immune cell that activated post transplantation. There are several subtypes of Th cells:
Th1: secret INFgama, IL-2 which activate CD8 cytotoxicity,macrophages, & production go IgG2 by Cells that activate complement, all these changes are associated with graft rejection.
Th2: produce IL-4, IL-5, IL-9, IL-10 & Il-13, these cytokines will activate B cells & induce rejection.
Th17: secret IL-17, IL-12, & Il-22, these cytokine act either alone or with other cytokine to increase neutrophil recruitment to site of rejection.
Th9: secret TGF-B & IL-4.
Tfh: it necessary in B cells differentiation, proliferation & maturation. It closely related to AMR after transplantation. Detection of IL-21 secreted by Tfh cells can predict the occurrence of AMR.
iTreg: it has an important & critical role in controlling immune responses & maintaining of immune tolerance.
References;
Handbook of Kidney Transplantation . 6th edition
Bhattacharyya N. & Fing C. Regulation of T Helper Cell Fate by TCR Signal Strength. Fort. Immune. 2020.
Luckheeram R., Zhou R., Verma A, er al. CD4 T cells: Differentiation and Functions. Clinical and Developmental Immunology. 2012
Issra F., Schiopu A. and Wood K. Role of T cells in graft rejection and transplantation tolerance. Expert Rev. Clinical. Immune. 2010, 6(1): 155-169.
saja Mohammed
3 years ago
What is the role of T helper cells (CD4) in the following?
Graft damage with emphasis on acute cellular and antibody mediated rejection
Induction of tolerance
-CD4+ T cells were functionally and phenotypically heterogeneous and capable of cross talk.
-CD4 T cells mediated delayed type hypersensitivity response (DTH) is sufficient to cause rejection without the need of cytolytic function of CD8 cells ,upon activation of CD4 produce subsets of cytokines to regulate the immune response which is antigen dependent stimulation.Activated APCs deliver three types of signals required for the clonal expansion and maturation of CD4+ T cells ,the first signal is mediated by the peptide-MHC interaction with the TCR,while the second involves costimulatory interactions between the APC and the T cell. The third signal directs differentiation of naive T cells to effector T cell subsets
-CD4 can further differentiated to subsets of cells:
-Type1Th cells secret cytokines like IL2,IL12 , INFγ, and TNF.
-Type2 Th cells secret cytokines like IL4,IL5,IL10 and 13 .
Its thoughts that Th1 activation can lead to rejection of the graft as type 1 cytokines promote effector functions such as DTH and cytolytic activity, promot cell mediated immunity ,enhance clearnce of intercellular pathogens and tumor cells ,opsonsing the AB production by B cells.
while Th2 responses might induce tolerance of the graft as the type 2 cytokines
antagonize the effectors and cytolytic activity, few studies shows that graft rejection associated with production of type1 and 2 cytokines while tolerance induced by inhibition of both types of cytokines.
-Th17 which produce cytokine 1L17 which have strong inflammatory effect that’s why the Th17 cells considered target for anti-rejection therapies .
-Th9 producing cells are proinflammatory as they stimulate proliferation and inhibit apoptosis of hematopoietic cells and also activate Th17 cells, -Th9, Th22, and IL-25 maintained mucosal immunity .
References :
1- hand book of kidney transplantion , Fifth-edithion Gabriel M.Danovitch
2-Review Article Functional and Phenotypic Plasticity of CD4+ T Cell Subsets
BioMed Research International Volume 2015, Article ID 521957, 13 pages http://dx.doi.org/10.1155/2015/521957.
Mahmoud Hamada
3 years ago
there are different types of T helper cells:
Type 1 —
release IL2 and IFN gamma – responsible of acute graft rejection through macrophage activation.
Type 2 —
Release interleukins 4,5,10 and 13. it promotes B cell function through IL4. TH2 is concerned with graft tolerance.
Type 17 —
Associated with graft rejection with a still to be completely understood mechanism. theories are Th17 increase cytokines e.g FGF, TGF-1. also, cyclosporine may increase cytokines and thus leads to allograft fibrosis.
Ref:
Uptodate.com Accessed 23/11/2021
Reem Younis
3 years ago
T lymphocytes are differentiated into multiple effector populations by cytokines that are either produced by antigen-presenting cells or activated T lymphocytes. CD4+ T lymphocytes differentiate into 4 major helper subsets and one regulatory subset, whereas CD8+ t lymphocytes differentiate into cytotoxic T cells. T helper lymphocytes :
T helper lymphocytes are the most important cell in adaptive immunity. Ther are classified into: Th 1 lymphocytes :
– Their differentiation depends on IL-12 and interferon-gamma also transcription factors STAT 1 and T-bet are necessary for their differentiation.
-They produce TNFα and lymphotoxin which activate macrophages and lead to allograft rejection.
-Ustekinumab, a monoclonal antibody against IL-12, was used in the treatment of psoriasis but not tested in transplantation. Th 2 lymphocytes:
– Their differentiation depends on IL-4 and transcription factors STAT6 and GATA3.
-They produce IL-4, IL-5, IL-9, IL-10, and IL-13, which activate eosinophil and basophil and mast cells and enhance the production of particular antibody isotypes.
-It is responsible for allergic reactions while IL-10 can dampen rejection.
-It inhibits Th 1 lymphocytes formation and delay rejection Th 17 lymphocytes :
– Their differention depends on TGFβ, IL-6, IL-21, and transcription factors STAT6 and RORɣT.
-It promotes inflammation by the production of IL-17. They respond to fungal infections.
They participate in the formation of tertiary lymphoid tissue at the site of chronic inflammation which is observed in renal allograft undergoing chronic rejection. T FH (Follicular helper)lymphocyte
-Their differention depends on IL-21 and transcription factors Bcl6.
-They provide help to B lymphocytes for antibodies production and drive alloantibodies which are determintal for graft survival. Th 9 lymphocyte :
– Their differention depends on IL-4 and TGFβ.
-They produce IL-9.
-It involves either immunity or tolerance. Treg FoxP3:
-Regulatory T cells (Treg )are a specialized subpopulation of T cells that act to suppress the immune response.
-It can inhibit T cells proliferation, cytokine production by T cells, and suppress B cells and dendritic cells.
– The most specific marker for these cells is FoxP3, which is localized intracellularly. References
1. Danovitch G.M handbook of kidney transplantation sixth edition
2.Veldhoen, Marc; Uyttenhove, Catherine; van Snick, Jacques; Helmby, Helena; Westendorf, Astrid; Buer, Jan; Martin, Bruno; Wilhelm, Christoph; Stockinger, Brigitta (December 2008). “Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset”. Nature Immunology. 9 (12): 1341–1346. doi:10.1038/ni.1659. ISSN 1529-2916. PMID 18931678. S2CID 205361860.
Ahmed Omar
3 years ago
Th are the key orchestrators of adaptive immunity , once activated they differentiate into a variety of effector cells that secrete various cytokines which can cause graft injury or induce tolerance.
The pattern of cytokine production defines the subset of T helper cells.
T lymphocytes populations and functions:
T helper (Th)1, Th2, Th9 and Th17 cells promote acute allograft rejection
regulatory T cells that are required to maintain self-tolerance
follicular helper T cells (TFH) that provide help to B cells for antibody production
TH1:responsible for graft rejection
Produces IFN-y, TNF alpha that activate macrophages, activate B lymphocytes that produce complement fixing IgG AB and stimulate differentiation of CD8 T cells to cytotoxic T cells
TH2: responsible for allergic reactions. They secrete IL-4 and IL-10 (and other cytokines) and help antigen-primed B lymphocytes differentiate into plasma cells and secrete antibodies, the effector molecules of humoral responses. (less potent than TH1)
TH9:They play a role in the immune response against tumor cells, allergy, and autoimmune disease
TH17: produce IL17 that can cause graft rejection by promoting inflammation and formation of tertiary lymphoid tissue at the inflammation site
Tfh (follicular): provide help for activated B lymphocyte to differentiate to AB producing plasma cells .
Memory T lymphocytes: few effector lymphocytes give rise to memory T cells which have longer life span, wider migration pattern, lower threshold for activation than naïve T cells with a stronger immune response that is partially responsive to co-stimulatory pathways as B7-CD28
Regulatory T cells (Tregs):usually secrete IL-10 and TGF beta (TGF β).They are specialized subpopulation of T cells that inhibit T cell proliferation cytokine production, preventing autoimmunity and down-regulate the allo-immune response
.
Tregs produce immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, that modulate APC functions, and can contribute to T effector cells suppression. So simply they are in charge of suppressing potentially deleterious activities of Th cells.
We conclude that the stimulatory activities of T cells in inducing allograft injury need to be counterbalanced by suppressive mechanisms, in order to fine-tune the immune responses and induce tolerance.
Plasticity of human CD4 T cell subsets. Jens Geginat et al. Front. Immunol., 16 December 2014
Hand book of renal transplantation, sixth edition
Immunopedia.og. overview of T cell subsets.
Weam Elnazer
3 years ago
CD4+ T-helper cells play an important role in alloimmune reactions the following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA.
Consequently, the reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcomes.
CD4+ T-helper cells are of significant importance during allograft rejection. During T-cell-mediated rejection, these cells are likely able to stimulate intermediary antigen-presenting cells, which can consequently prime CD8+ cytotoxic T-cells.
In the formation of HLA antibodies, CD4+ T-helper cells can stimulate B-cell proliferation and differentiation. More specifically, CD4+ T-helper cells may recognize epitopes derived from mismatched HLA via the indirect pathway of allorecognition.
In this process of indirect allorecognition, mismatched HLA molecules are internalized and processed into peptide fragments by antigen-presenting cells such as B cells.
These HLA-derived peptides are subsequently presented on the cell surface of these antigen-presenting cells by HLA class II molecules. The CD4+ T-helper cells, in turn, recognize these allopeptide-HLA class II complexes and provide help to naive B cells by stimulating B-cell proliferation, differentiation of naive B cells into antibody-producing plasma cells and memory B cells, and immunoglobulin class switching.
Thus, these CD4+ T-helper cells may contribute to the formation of de novo DSA.
Schoenberger SP, Toes REM, van der Voort EIH, Offringa R. Melief CJM. T-Cell Help for Cytotoxic T Lymphocytes is Mediated by CD40–CD40L Interactions. Nature (1998) 393(6684):480–3. doi: 10.1038/31002
Lee RS, Grusby MJ, Glimcher LH, Winn HJ, Auchincloss H. Indirect Recognition by Helper Cells can Induce Donor-Specific Cytotoxic T Lymphocytes In Vivo. J Exp Med (1994) 179(3):865–72. doi: 10.1084/jem.179.3.865
Suciu-Foca N, Ciubotariu R, Itescu S, Rose E, Cortesini R. Indirect Allorecognition of Donor HLA-DR Peptides in Chronic Rejection of Heart Allografts. Transplant Proc (1998) 30(8):3999–4000. doi: 10.1016/S0041-1345(98)01318-9
21. Liu Z, Colovai AI, Tugulea S, Reed EF, Fisher PE, Mancini D, et al. Indirect Recognition of Donor HLA-DR Peptides in Organ Allograft Rejection. J Clin Invest (1996) 98(5):1150–7. doi: 10.1172/JCI118898
Heba Wagdy
3 years ago
T helper cells play a role in cellular rejection and antibody mediated rejection, they provide help to CD8+ T cells so help graft directed CD8+ T cell response.(1)
CD4 T helper cells have an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching. (2)
Subtypes of T helper cells:
Th1 cells:
Secrete growth factor IL2 that increase proliferation of cytotoxic CD8+ T cells after allogenic stimulation. (3)
Induce delayed type hypersensitivity by macrophages and activate B cells to produce antibodies (3)
Th2 cells:
produce cytokines that facilitate humoral response particularly IgE production and activate eosinophils which may have a role in allograft rejection. (4)
Th17 cells:
secrete IL17 which has ability to recruit neutrophils, one of the first inflammatory effector cells to infiltrate allograft and cause damage. (5)
Th9 cells:
associated with variety of inflammatory diseases, involved in regulation of allergic inflammatory response which could be involved in allograft rejection.(6)
Th22 cells:
Have an important role in epidermal immunity, remodeling and auto immune disease. (7)
T follicular helper cells:
express CXCR5 which allow trafficking to B cell follicles, promote germinal center formation by providing help to B cells enabling their proliferation and differentiation into memory B cells & plasma cells that secrete high affinity antibodies. (8)
constitute a memory pool that recirculate in blood and is inactive in absence of antigen stimulation. (9)
Regulatory T cells:
important in mediating immune tolerance to self antigens
CD4+ CD25+Foxp3+ natural Tregs play a role in suppression of self reactive cells and are associated with better graft survival. (10)
The suppressive effects include secretion of anti-inflammatory cytokines, inhibition of T cell activation via tumor growth factor B, silence T cell genes responsible for production of cytokines via exosome carried microRNA, suppression of APC via CTLA-4 and induction of apoptosis via granzyme A/B, perforins & inducible cAMP. (11)
(1) Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol (2016) 7:582.
(2) Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH, et al. Two levels of help for B cell alloantibody production. J Exp Med (1996) 183:699–703
(3) Jiang S, Herrera O, Lechler RI. New spectrum ofallorecognition pathways: implications for graftrejection and transplantat ion tolerance. Curr OpinImmunol 2004;16:550–557
(4) Goldman M, Le Moine A, Braun M, Flamand V,Abramowicz D. A role for eosinophils intransplant rejection. Trends Immunol2001;22:247–251
(5) Agorogiannis, E.I., Regateiro, F.S., Howie, D., Waldmann, H. & Cobbold, S.P. (2012) Th17 cells induce a distinct graft rejection response that does not require IL-17A. American Journal of Transplantation, 12, 835.
(6)Askar, M., 2014. T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation. International journal of immunogenetics, 41(3), pp.185-194.
(7) Eyerich, S., Eyerich, K., Pennino, D., Carbone, T., Nasorri, F.,Pallotta, S. et al. (2009) Th22 cells represent a distinct humanT cell subset involved in epidermal immunity and remodeling.The Journal of Clinical Investigation, 119, 3573
(8) Crotty S: T follicular helper cell differentiation, function, and roles in
disease. Immunity 41: 529–542, 2014
(9) Asrir A, Aloulou M, Gador M, Pérals C, Fazilleau N: Interconnected subsets of memory follicular helper T cells have different effector functions. Nat Commun 8: 847, 2017
(10) L. Ma, H. Zhang, K. Hu, G. Lv, Y. Fu, D.A. Ayana, P. Zhao, Y. Jiang, The imbalance between Tregs, Th17 cells and inflammatory cytokines among renal transplant recipients, BMC Immunol. 16 (1) (2015) 56
(11) T. Vaikunthanathan, N. Safinia, D. Boardman, R.I. Lechler, G. Lombardi, Regulatory T cells: tolerance induction in solid organ transplantation, Clin. Exp. Immunol. 189 (2017) 197.
Last edited 3 years ago by Heba Wagdy
Mohamad Habli
3 years ago
After activation of T cell by APC and initiation of the 3 signals, CD4+ T lymphocytes differentiate into several subclasses of T helpers and one regulatory subpopulation (T- reg), while CD8+ differentiate into cytotoxic T cell TCL.
Activated CD4+ T cells are subdivided into distinct functional categories depending on types cytokines secreted. The type of activated cells also depends on the site of antigen entry, the route of entry, the form of the antigen, and the amount of antigen.
Types of T helper cells:
Th1 — Th1 cells secrete IFN-gamma and IL-2. Th1 are involved in cellular cytotoxic response and activation of macrophages. T helper type 1 response is also responsible of antibodies production in particular IgG1.
Th2 — T helpers type 2 are involved in the development of allergic reaction through promotion of IgE and eosinophil activation. Th2 cells have major role in the development of asthma. Th2 cells produce IL-4, IL-5, IL-13, and IL-10. Th2 cells are active against parasitic infections.
Th17 — T helper type 17 cells secrete IL-17A, which induces production of pro inflammatory cytokines (IL-17F, IL-22, IL-26) and chemokines (CCL20) and recruits neutrophils .They have antibacterial and antifungal immune effect and involved in immune response in the settings of autoimmune diseases or chronic infections.
Th9– These cells have a role in autoimmune disease, anti-cancer and allergy. T helper type 9 cells produce IL-9 and IL-10. Th9 activation has a negative effect on the expression of CD40L in CD4 cells which cause reduced binding to the CD40 cells (B cells,DC and macrophages leading to decreased B cell expansion and IgG production.
Th22–Th22 cells are a major source of IL-22, although this cytokine is also produced by Th17. Th22 cells canhave a protective role in mucosal immunity cells, but deleterious effect in combination with IL17 causing autoimmune and inflammatory diseases, in particular psoriasis.
iTreg — Induced T regulatory (iTreg) cells can be induced in the periphery after antigen priming in the presence of retinoic acid and TGF-beta.
Tfh — T follicular helper (Tfh) cells are predominant in the secondary lymphoid organs. Tfh are activated by IL12.Upon activation, follicular T helpers have high affinity to bind B cells and subsequent differentiation and production of antibodies.
Tregs– are a specialized subpopulation of T cells that suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, NK cells, and Antigen Presenting Cells (APCs), thereby maintain the critical balance between selftolerance and autoimmunity. Tregs produce immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, that modulate APC functions, and can contribute to T effector cells suppression.
Th3 — T helper type 3 (Th3) cells are important in development and maintenance of induced Treg cells.
In clinical practice, the type of T helpers determines the activity of immune response as some of them induce B cells activation an maturation and subsequent antibody production and eventually AMR ( Th1, Th2, Th9, Th17, Th22, Thf) while others have role in immunosuppression and immunomodulation (Treg, iTreg, Th3).
Antibody molecules that are produced by plasma cells, represent an advanced stage in the B-cell development. After recognition of APC by TCR, and activation of T cells and further differentiation, and binding of Th CD4, the costimulatory pathway of CD40-CD40L is responsible for activation of B cells and differentiation into plasma cells, which are capable of antibody production and development of antibody mediated rejection.
References:
Handbook of kidney transplantation 6th edition
Uptodate
Sherif Yusuf
3 years ago
CD4 positive T cells is activated if APC express antigen in complexes with HLA class II
T helper cells which activate immune response and aid in rejection are :
1- T helper 1 which secrete IFN-gamma and IL-2 produce the following :
Activate macrophage leading to delayed type hypersensitivity
Activate cytotoxic T cells that induce T cell medicated cytotoxicity by either lysis or induced apoptosis
Stimulate B cells to secrete IgG antibodies.
So it is the main mediator of cell mediated and antibody medicated rejection
2- T helper 2 which secrete IL-4, IL-5, and IL-13 that promote production of antibodies mainly IGE from plasma cells and are responsible for IgE-mediated atopic disease, immunity against parasitic infestations. (1)
3- T follicular helper provide help to B cells for production of antibodies, termed follicular because they are predominant in secondary lymphoid tissue
4- T helper 17 that secretes IL-17 which cause recruitment of neutrophils, responsible for immunity against extracellular bacteria and fungi and autoimmunity and play an impotent rule in graft rejection (2)
5- T helper 22 which secrete IL 22 which augment inflammatory effect of IL 17 secreted by T helper 17 when secreted with IL 17, has great importance in psoriasis, atopic dermatitis, bronchial asthma and has protective rule in mucosal immunity. (3)
6- T helper 9 secretes IL-9, IL 10, they have an important rule in allergy, autoimmune disease and immunity against tumors (4)
T helper cells which suppress immune response and aid in tolerance are :
1- Regulatory T cells which suppress the immune response and play main rule in maintenance of peripheral tolerance, although some express CD4 but others express CD25 or and Foxp3 (5)
2- Induced T regulatory (iTreg) cells which are regulatory T cells that are induced in the periphery after priming of antigen.
3- T helper type 3 (Th3) cells which are important for induction of mucosal tolerance and aid help for maintenance and development of induced T regulatory cells (6).
REFERANCES
1. Hancock WW, Sayegh MH, Kwok CA, et al. Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation. Transplantation 1993; 55:1112.
2. Chadha R, Heidt S, Jones ND, Wood KJ. Th17: contributors to allograft rejection and a barrier to the induction of transplantation tolerance? Transplantation 2011; 91:939.
3. Plank MW, Kaiko GE, Maltby S, et al. Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity. J Immunol 2017; 198:2182.
4- Schmitt E, Klein M, Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol 2014; 35:61.
5- Tsaur I, Gasser M, Aviles B, et al. Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. Kidney Int 2011; 79:1005.
6- Carrier Y, Yuan J, Kuchroo VK, Weiner HL. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol 2007; 178:179.
The activated CD4+ T lymphocytes can differentiate into several distinct subtypes, which differ in their action and active immune mediators secreted (1). A collective summary of T cell differentiation is illustrated in the attached figure (1).
· T helper type 1 (Th1):
It acts via induction of cellular cytotoxicity and macrophage activation. Thus, it plays an essential role in eradicating intra-cellular organisms e.g viruses and mycobacteria and stimulating cytotoxic T cell maturation.
· T helper type 2 (Th2):
It is believed to play an important role in the immune response against parasitic infestations, particularly helminths, and they may have a role in the development of allergy and asthma
· T helper type 9 (Th9):
They are thought to have a role in the immune response against tumour cells, allergy, and autoimmune disease
· T helper type 17 (Th17):
It is thought to play a role in the immune response against extracellular pathogens like bacteria and fungi. Additionally, it may have a role in chronic inflammatory responses in chronic infection, allergy, and autoimmunity.
· T follicular helper (Tfh):
It is believed to have a role in activating B lymphocytes and augmentation of antibody production.
· T regulatory (Treg):
It is thought to be essential in developing and maintaining peripheral tolerance by negative feedback suppression of the immune response. It represents typically 1-2 % of the total CD4 population.
· Induced T regulatory (iTreg):
It can be induced in the periphery after antigen priming in the presence of TGF-beta.
· T helper type 3 (Th3):
It plays a role in mucosal tolerance induction and may promote the development and/or maintenance of induced Treg cells.
T helper cells differentiate into 4 major helper cells( Th1, Th2, Th17 & Thf) and one regulatory cell type( Treg).
Th1: is the prototype responsible for rejection.it produce IFNg, TNF alpha and lymphotoxin which promote allograft rejection by activating macrophages, directly damaging the endothelium, production of complement fixing IgG ab by B lymphocytes and stimulate the differentiation of CD8+ T lymphocytes to cytotoxic T lymphocytes.
Th2: responsible for allergic reaction but also have a role in rejection. They produce a variety of interleukins that activate eosinophils, basophils, and mast cells and enhance the production of ab.s that do not fix complement.
Th17: they produce IL 17 and promote allograft rejection by inducing inflammation
TFH: they provide help for B lymphocytes for ab production.
CD4+ T helper cells do not generally induce allograft rejection, their greater role in rejection is through providing help for cytotoxic CD8+ T cells.
Tregs which is CD54+ FOXP3+ T cells, provide potential control of alloimmunity and induction of tolerance through absorption of pro inflammatory IL2, CTLA4 mediated masking of CD80 & CD86 costimulatory ligand on antigen presenting cells, expression of immune inhibitory molecules & granzyme mediated killing of antigen presenting cells.
References:
Handbook of kidney transplantation by G.M. Danovitch, sixth edition
Siu J.H.Y., Surendrakumar V., Richards J.A., Pettigrew G.J. T cell Allorecognition Pathways in Solid Organ Transplantation.Front. Immunol., 05 November 2018.
Th9 is a functional subgroup of CD4+ T cells
It was first discovered at 2008.
Differentiated by cytokine transforming growth factor beta & IL4
PU.1 is a specific transcription factor for Th9 differentiation
Secret IL9 and recruit mast cells
Play important role in inflammatory diseases, autoimmune diseases, tumors.
Reference:
Chen J., Guan L., Tang L., Liu Sh. T Helper 9 Cells: A New Player in Immune-Related Diseases. DNA AND CELL BIOLOGY . 2019,Volume 38, Number 10.
Riham Marzouk
3 years ago
T helper cells express CD4, which is membrane glycoprotein, associated with T cell receptor (TCR), which facilitate binding of TCR to MHC II molecule.
Antigen binding to MHC II on dendritic cells leads to activation of naiive T helper cells to proliferate much more, then T helper cells will activate APCs like macrophages, dendritic cells and B cells as they express MHC II molecule and initiate its immune response.
CD4 cells or T helper cells have several subtypes, every type secrete different cytokines sharing in immune response.
CD4 cells activate cytotoxic cells , and APCs like macrophage and B cells and lead to its maturation and antibody formation.
CD4 protein bind also to HIV glycoprotein and all immunoglobulin classes.
CD4 cells which express CD25+ and has nucleated transcription factor FoxP3 are considered Treg cells which regulate and inhibit immune response and has a central role in immune tolerance
CD4 can recognize MHC II on donor APCs through TCR, and also recipient APCs can processed and present donor antigen to CD4 cells.
activation of CD4 will also activate CD8 which recognize MHC I of donor APCs.
also activated CD4 will stimulate and activate B cells to secrete antibodies ( B cells also is recipient APCs which processed and present donor antigen to CD4 cells).
T cells will not be fully activated except after 3 signals stimulation:
1- signal 1 through interaction or conjunction between TCR and MHC I (CD8), and MHC II ( CD4) on APCs.
2- signal 2 interaction between receptors CD28 (on T cells) and CD80/86/B7 on APCs upon another lock between CD154 (on T cells) and CD40 (on APCs )….co stimulatory pathway.
3- signal 3 interaction between CD25 on T cells and IL-2.
all these will stimulate T cells to produce cytokines and induce T cells proliferation, these cytokines will stimulate macrophages and B cells to produce antibodies (alloantibodies).
in very early period post-transplantation, the effect of ischemia will affect CD4 function and activation as ischemia will increase expression of HLA antigen and increase co stimulator proteins.
endothelial cells in the graft express MHC II which will be attacked by CD4 ends by antibodies formation and complement system activation with vascular injury and c4d deposition in antibody mediated rejection.
Treg cells is one of helper cell subsets, and responsible for immune induction
Treg cells, subsets of T cells inhibit or regulate function of other immune cells so inhibit immune response to self and non-self antigens so prevent autoimmune diseases. It comes from differentiation of naiive Tcells outside thymus (periphery), and responsible for maintenance of peripheral tolerance, and has anti-tumor function.
Treg are CD4+CD25+, they express nuclear transcription factor FoxP3 which is responsible for its regulatory inhibitory function of Treg and can be used as a marker to monitor Treg post transplant.
Treg cells were activated by :
1- IL-2 lead to its clonal expansion and increased its number.
2- CD28 costimulation will lead to IL-2 secretion which increase Treg numbers.
Mechanism of Treg cells in inducing immune tolerance:
1- Release of inhibitory cytokines like IL-10, TGF-β and IL-35.
2- Treg cells mediate cell lysis by certain mediators like granzyme A and B , and perforin.
3- Apoptosis mediated by cytokine deprived state as Treg cells consume IL-2.
4- Modulate dendritic cell maturation or function; cytotoxic T lymphocyte antigen 4 (CTLA-4) interacts with CD-80/CD-86 and produce inhibitory pro apoptotic molecules.
Subsets of CD4+ cells
classical T-helper 1(Th1)
T-helper 2 (Th2) cells
T-helper 17(Th17)
follicular helper T cell (Tfh)
induced T-regulatory cells (iTreg)
regulatory type 1 cells (Tr1)
T-helper 9 (Th9)
Th1 Cells.
Th1 cells are involved with the elimination of intracellular pathogens and
Also are associated with organ specific autoimmunity
They secrete IFNγ, lymphotoxin α (Lfα), and IL2.
IFNγ is essential for the activation of mononuclear phagocytes. IFNγ is believed to exert its effect through
Lfα is associated with autoimmune diseases.
IL2 promotes proliferation of CD8+T cells with acquisition of cytolytic phenotype .
Besides its role as T cell growth factor, IL2 promotes the development of CD8+ memory cells after
antigen priming. Natural Treg (thymus derived) need IL2 for survival and activation.
Th2 Cells.
Th2 cells mount immune response to extracellular parasites, including helminthes.
The key effector-cytokines include IL4, IL5, IL9, IL13, IL10, IL25, and amphiregulin.
IL4 -involved in allergic inflammation
IL5- leads to activation and upregulation of eosinophils.
IL9-activates the function of mast cells, B cells,eosinophils, neutrophils as well as airway epithelial cells.
IL10- is an anti-inflammatory cytokine
IL13- combats gastrointestinal helminthes.
IL25- promotes Th2 responses, suppress Th17 response.
Th17 Cells
mount immune response against extracellular bacteria and fungi.
also involved in the generation of autoimmune diseases.
The key effector cytokines include IL17A, IL17F,IL21, and IL22.
Show plasticity .
Regulatory CD4+T Cells
Treg exists as natural thymus derived subset with expressed FOXP3
and as peripheral induced Treg cells, which arise from naıve CD4+CD25-cells.
Treg and Tr1 play important role in the maintenance of immunologic tolerance to self and foreign antigen.
effector cytokines include IL10, TGF β, and IL35.
Show plasticity and can reprogram into proinflammatory phenotypes in the presence of relevant cytokine milieu and cause more harm.
Follicular Helper (Tfh) T Cells.
play significant role in mediating humoral immunity through interaction with B-lymphocytes.
B cells undergo subsequent differentiation into Ig-producing plasma cells.
In the germinal area, they develop into B memory cells.
Tfh cells have been classified into Tfh1, Tfh2, and Tfh10.
Th9
Are a relatively new member in the Th cell family.
The signature cytokine for Th9 cells is IL-9, a cytokine in the IL-2Rγc-chain family.
Functionally, Th9 cells promote immune tolerance and protect against parasitic infections .
They also exert strong anti-tumor immunity.
Th9 cells also trigger prominent allergic inflammation, asthma, and autoimmune diseases, highlighting their pathological roles in the immune system.
T helper type 1 (Th1):
It induce cellular cytotoxicity and can activate the macrophage. It eradicate intra-cellular organism and stimulate cytotoxic T-cell maturation.
T helper type 2 (Th2):
It is importance in the immune response against parasitic infestation .It have a role in the development of allergy .
·T helper type 9 (Th9):
They are thought to have a role in the immune response against tumour cells, allergy, and autoimmune disease
T helper type 17 (Th17):
It is responsible for immune response against extracellular pathogens like bacteria and fungi. It have a role in chronic inflammatory responses in chronic infection, allergy, and autoimmunity.
T follicular helper (Tfh):
It is found to have a role in activating B lymphocytes and antibody production.
T regulatory (Treg):
It is responsible for developing and maintaining peripheral tolerance by negative feedback suppression of the immune response.
References:
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer
Jennifer Heimall. The adaptive cellular immune response: T cells and cytokines. © 2021 UpToDate. (Accessed on 21 November 2021)
T cells CD4+ are differentiated in subtypes.
Th1cels act through cytotoxicity and macrophage activation ,thus having intracellular antimicrobial effect
Th2 cells have anthelmintic action and a role in asthma and allergy.
Th9 cells have antitumor action and have role in allergy and autoimmune disease.
Th17could have action against extracellular pathogens and role in chronic inflammation and autoimmunity.
Th follicular activating B lymphocytes and antibody production.
T reg essential for peripheral tolerance through suppression of immune response.
iTeg induced following antigen priming with TGFB.
Th3 have role in mucosal tolerance and development and /or maintenance of iT reg cells.
REFERENCES:
Heimall ,J: The adaptive cellular immune response : T cells and cytokines,Uptodate,Nov,2021.
Activated CD4 T lymphocytes can differentiate into several distinct subtypes:
* T helper type 1:
Stimulate cellular cytotoxicity and macrophage activation. Thus, it plays an essential role in elimination of intra-cellular organisms.
*T helper type 2:
They may have a role in the development of allergy and immune response against parasitic infestations.
*T helper type 9:
They have a role in the immune response against tumor cells, allergy, and autoimmune disease
*T helper type 17:
It is believed to play a role in the immune response against extracellular pathogens like bacteria and fungi.
*T follicular helper:
It is believed to have a role in activating B lymphocytes and increased antibody production.
*T regulatory:
Vital in developing and maintaining peripheral tolerance by negative feedback suppression of the immune response.
Role of T helper in graft damage with acute cellular and antibodies mediated Rejection.
CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment.
*** Lymphopoiesis:
T cells precursors originating from a common lymphoid hematopoietic stem cell leave the bone marrow to reach the thymus for maturation. Initially thought to be an evolutionary remnant with negligible function, the thymus is in fact a primary lymphoid organ indispensable for T-lymphocyte development.
**CD4+T Cells Activation and Differentiation:
The initial step of differentiation of the naïve cells is the antigenic stimulation as a result of interaction of TCR and CD4 as co-receptor with antigen-MHC II complex, presented by professional antigen presenting cells (APCs). TCR coupled with CD3 activation consequently induces a network of downstream signaling pathways, that eventually lead to naïve cell proliferation and differentiation into specific effector cells.
**Th1 Differentiation:
Interleukin 12 (IL12) and interferon γ (IFNγ) are the critical cytokines initiating the downstream signaling cascade to develop Th1 cells . IL12 is secreted in large amounts by APCs after their activation through the pattern recognition receptors .The IL12, in turn, induces natural killer cells(NK) to produce IFNγ.
***Th2 Differentiation
IL4 and IL2 are critical for Th2 differentiation. The major transcription factor involved in Th2 lineage differentiation includes the IL4-induced STAT6, which upregulates the expression of the master regulator GATA3 (GATA-binding protein) .3 distinct mechanisms of GATA3 involvement in Th2 differentiation have been postulated, including enhanced Th2 cytokine production, selective proliferation of Th2 cells through recruitment of Gfi-1, and inhibition of Th1 differentiation presumably by interacting with T-bet.
**Th9 Cells:
Initially characterized as a subset of Th2 cells, ongoing researches tend to classify IL9 secreting-Th9 cells as a distinct subset of CD4+ T cells.
***Th17 Cells Differentiation:
IL6, IL21, IL23, and TGF-β are the major signaling cytokines involved in Th17 cells differentiation, and retinoic acid receptor-related orphan receptor gamma-T (RORγt) is the master regulator.
***Regulatory Cells Differentiation:
iTreg cells are FOXP3+CD4+CD25+ cells, which are developed in the peripheral lymphoid organs after antigen priming, in contrast to the natural Treg (nTreg) which are released from the thymus as a distinct lineage with FOXP3 already expressed
***Follicular Helper (Tfh) T Cells:
Tfh are C-X-C motif receptor-5 (CXCR 5+) expressing cells and are located in follicular areas of lymphoid tissue, where they participate in the development of antigen-specific B-cell immunity .IL6 and IL21 are the main cytokines involved in the differentiation process .STAT3, activated downstream to cytokine signaling, is an important transcription factor of Tfh. However, unlike in Th17 development, TGFβ does not participate, and RORγt is not induced. In vitro, IL21 in the absence of TGFβ resulted in Tfh differentiation.
*** Plasticity of CD4+ Cells:
Unlike Th1 and Th2 cells, which are considered to be terminally differentiated, Th17 and Treg have shown plasticity, thereby suggesting that they are not terminally differentiated.
~Effector Functions>>>
***Th1 Cells:
Th1 cells are involved with the elimination of intracellular pathogens and are associated with organ-specific autoimmunity [114]. They mainly secrete IFNγ, lymphotoxin α (Lfα), and IL2. IFNγ is essential for the activation of mononuclear phagocytes, including macrophages, microglial cells, thereby resulting in enhanced phagocytic activity .
*** Th2 Cells:
Th2 cells mount immune response to extracellular parasites, including helminthes, and play major role in induction and persistence of asthma as well as other allergic diseases . The key effector-cytokines include IL4, IL5, IL9, IL13, IL10, IL25, and amphiregulin. IL4 is a major cytokine involved in allergic inflammation. It is involved in IgE switching and secretion by B cells.
*** Th17 Cells:
Th17 is responsible to mount immune response against extracellular bacteria and fungi. They are also involved in the generation of autoimmune diseases .The key effector cytokines include IL17A, IL17F, IL21, and IL22. IL17A and IL17F signaling occurs through a common receptor, IL17RA, thereby suggesting similar functions.
*** Regulatory CD4+T Cells:
Treg exists as natural thymus-derived subset with expressed FOXP3, and as peripheral-induced Treg cells, which arise from naïve CD4+CD25-cells after antigen priming in a relevant cytokine milieu .Treg and Tr1 play important role in the maintenance of immunologic tolerance to self and foreign antigen.
***Follicular Helper (Tfh) T Cells:
After TCR interaction and subsequent differentiation from the CXCR5−CCR7+CD4+ naïve cells, these CXCR5+CD4+T (Tfh) cells play significant role in mediating humoral immunity through interaction with B-lymphocytes. After having lost CCR7, the differentiated CXCR5+CCR7-pMHCII-specific Tfh cells enter the pregerminal centre for initial interaction with antigen-primed B cell,
References:
1. Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nature Reviews Immunology.
2. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R. Thymic generation and regeneration. Immunological Reviews. 2003;195:28–50.
3. Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature Reviews Immunology. 2006;6(2):127.
4. Daniels MA, Teixeiro E, Gill J, et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature. 2006;444(7120):724–729.
5. Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors. Annual Review of Immunology. 2006;24:419–466.
1- Graft damage with emphasis on acute cellular and antibody mediated rejection :
2- Induction of tolerance :
Allograft rejection is primarily driven by the ability of host T cells to recognize
polymorphisms encoded within the MHC as well as multiple minor histocompatibility loci.
While all components of the innate and adaptive immune systems participate in graft
rejection, T lymphocytes and particularly CD4 T cells play important role in this process
In this process.
Rejection reaction consists of the sensitization stage and the effector stage.
Sensitization stage:
In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the
alloantigen expressed on the cells of the foreign graft.
Two signals are needed for recognition of an antigen; the first is provided by the
interaction of the T cell receptor with the antigen presented by MHC molecules, the
second by a costimulatory receptor/ligand interaction on the T cell/APC surface.
Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface
with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86,
respectively), has been studied the most.
In addition, cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these
ligands and provides an inhibitory signal.
Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).
Effector stage:
Alloantigen-dependent and independent factors contribute to the effector mechanisms.
Initially, ischemia induce a nonspecific inflammatory response.
Because of this, antigen presentation to T cells is increased as the expression of
adhesion molecules, class II MHC, chemokines, and cytokines is upregulated.
It also promotes the shedding of intact, soluble MHC molecules that may activate the
indirect allorecognition pathway. After activation, CD4-positive T cells initiate
macrophage-mediated delayed type hypersensitivity responses and provide help to B
cells for antibody production.
Host T cells can be activated in response to an allogeneic stimulus by one of two
separate mechanisms:
Direct allorecognition:
It’s the response of host T cells recognizing intact donor MHC molecules present on the
surface of donor-derived antigen-presenting cells (APCs).
Indirect pathway:
Host T cells respond to processed donor-derived peptides bound to syngeneic MHC
molecules and presented in a self-restricted manner.
During acute rejection:
Donor-derived APCs, primarily dendritic cells, are present in grafted tissues as
passenger leucocytes that migrate post-transplant to host lymphoid tissues where they
directly stimulate host T cells. Dendritic cells are extremely powerful activators of naive
T cells, and this, coupled with the very large frequency of cells exhibiting direct
alloreactivity, has led to the concept that the direct pathway of allorecognition is
dominant way in acute rejection.
Chronic rejection:
The indirect pathway predominate in the later stages of the allograft response.
Evidence in favor of this includes the findings of large numbers of indirectly reactive T
cells (by limiting dilution analysis) in patients undergoing chronic rejection.
Direct alloreactivity may not necessarily be limited to the early phases, Donor endothelial
cells, expressing many of the same costimulatory and adhesion molecules found on
dendritic cells, are able to directly activate recipient CD8 T cells.
Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early
after transplantation, endothelial cells activated by T cell–derived cytokines and
macrophages express class II MHC, adhesion molecules, and costimulatory molecules.
These can present antigen and thereby recruit more T cells, amplifying the rejection
process.
Apoptosis:
The final common pathway for the cytolytic processes is triggering of apoptosis in the
target cell.
Tolerance:
Central (Intrathymic) Mechanisms of Tolerance:
The chief mechanism of T-cell tolerance is the deletion of autoreactive T cells in the
thymus so that the organism is rendered self-tolerant.
Peripheral (Nonthymic) Mechanisms of Tolerance:
many antigens are absent intrathymically or present at insufficient levels to induce
tolerance in the thymus.
References:
1- Patrick T. Walsh ,Terry B. Strom, and Laurence A. Turka. Routes to Transplant
Tolerance versus Rejection: The Role of Cytokines. Immunity. 2004 Feb; 20(2): 121 -131.
2- Prashant Malhotra, FIDSA; Ron Shapiro et al. Immunology of Transplant Rejection,
Medscape, Oct 16, 2019.
Helper T cells are the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells.
Helper T cells themselves, however, can only function when activated to become effector cells. They are activated on the surface of antigen-presenting cells, which mature during the innate immune responses triggered by an infection. The innate responses also dictate what kind of effector cell a helper T cell will develop into and thereby determine the nature of the adaptive immune response elicited.
the T cell can differentiate into either a TH1 or TH2 effector helper cell. These two types of functionally distinct subclasses of effector helper T cells can be distinguished by the cytokines they secrete. If the cell differentiates into a TH1 cell, it will secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and will activate macrophages to kill microbes located within the macrophages’ phagosomes. It will also activate cytotoxic T cells to kill infected cells. Although, in these ways, TH1 cells mainly defend an animal against intracellular pathogens, they may also stimulate B cells to secrete specific subclasses of IgG antibodies that can coat extracellular microbes and activate complement.
●Naïve T cells require at least two signals for activation. Both are provided by an antigen-presenting cell, which is usually a dendritic cell: signal 1 is provided by MHC-peptide complexes binding to T cell receptors, while signal 2 is mainly provided by B7 costimulatory proteins binding to CD28 on the T cell surface. If the T cell receives only signal 1, it is usually deleted or inactivated. When helper T cells are initially activated on a dendritic cell, they can differentiate into either TH1 or TH2 effector cells, depending on the cytokines in their environment: TH1 cells activate macrophages, cytotoxic T cells, and B cells, while TH2 cells mainly activate B cells. In both cases, the effector helper T cells recognize the same complex of foreign peptide and class II MHC protein on the target cell surface as they initially recognized on the dendritic cell that activated them. They activate their target cells by a combination of membrane-bound and secreted signal proteins. The membrane-bound signal is CD40 ligand. Like T cells, B cells require two simultaneous signals for activation. Antigen binding to the B cell antigen receptors provides signal 1, while effector helper T cells provide signal 2 in the form of CD40 ligand and various cytokines.
Most of the proteins involved in cell-cell recognition and antigen recognition in the immune system, including antibodies, T cell receptors, and MHC proteins, as well as the various co-receptors discussed in this chapter, belong to the ancient Ig superfamily. This superfamily is thought to have evolved from a primordial gene encoding a single Ig-like domain.
Reference
https://www.ncbi.nlm.nih.gov/books/NBK26827/
CD4+ T cell in the alloresponse
• CD4+ T cells are important to allograft destruction
Th1
• induces cell mediated immunity – producing IFN-g and IL-2 which stimulate activation of CD8+ cytotoxicity, macrophages -dependant delayed type hypersensitivity and the production of IgG2a by B cells,thus initiates complement which associated with allograft rejection
• may express FasL, enable them to exhibit cytotoxic activity
Th2
• Humoral immunity is driven by Th2 cells
• The type of T helper cell response is determined by the microenvironment in which APC and T cell interactions take place
• Secrete IL-4,IL-5,IL-9,IL-10 and IL-13- activate B cells and eosinophils to promote graft rejection
Th17
• produces IL-17,IL-21 and IL-22 which act alone and synergistically have shown to have impact in allograft rejection altering the Th1/Th2 paradigm
CD4+ T cell in regulation and transplant tolerance
CD4+CD25hiFoxP3+ Tregs( nTreg)
• express high levels of CD25 ( IL-2 receptor alpha chain) on the surface,thus provide a marker for isolation and characterisation
Adaptive ( induced) Tregs
• generated in the periphery by induction of FoxP3 expression in CD4+CD25- or CD4+CD25+ FoxP3-T cells
• Tr1 equipped a FoxP3- independent paracrine suppression mechanism regulated by the inhibitory cytokines IL-10 and TGF-beta to initiate immunoregulatory functions
References
Issa, F., Schiopu, A. and Wood, K., 2010. Role of T cells in graft rejection and transplantation tolerance. Expert Review of Clinical Immunology, 6(1), pp.155-169.
References ;
the exogenous antigen is presented on class II molecules—which are then recognized by CD4+ (i.e., expressing CD4 antigen) T helper cells. Activated T helper cells produce cytokines, which promote T-cell proliferation and differentiation, induce antibody secretion by B cells, and induce cytotoxicity in macrophages, natural killer cells, and cytotoxic T cells. Antigen specifi city is provided by clonally restricted T-cell receptors (TCRs) which recognize a peptide-HLA complex.
CD4 acts as a co-receptor, bringing the required proteins for activation into proximity of the TCR complex. Stimulation of the TCR results in phosphorylation of many proteins and activation of second messenger systems. This, together with a rise in intracellular calcium, activates the DNA-binding factors needed for IL-2 transcription and activates calcineurin—which through the modifi cation of the nuclear factor of activated T cells results in the formation of the functional protein that promotes IL-2 gene transcription. For complete recognition and response to alloantigen, at least two signals are required.
The most studied and potent costimulatory pathway is the CD28-B7 ligand receptor binding. Without stimulation of both signals, there is immune anergy.
The local cytokine milieu and the antigen presented result in the differentiation of naive T helper cells into Th1 or Th2 cell subsets, which secrete different cytokines and hence have different functions.
Th1 cells are mainly involved in
cell-mediated immunity, whereas Th2 cells are involved in humoral immunity. The recruitment, proliferation, and differentiation of leukocytes in rejection are all dependent on cytokine and chemokine production. Chemokines also facilitate adhesion of the leukocytes to the endothelial wall prior to diapedesis into the tissue, either directly or by activating integrins or adhesion molecules.
Antibody-Mediated Rejection
Acute humoral rejection, beyond the immediate reperfusion period, can be diffi cult to diagnose because it may manifest as acute tubular injury with no evidence of circulating antibodies. This is not to say that antibodies are not present but rather that the currently available techniques are not sensitive enough to detect them. Other suggested explanations for the lack of detectable antibodies include that the graft absorbs the antibodies (removing them from the plasma) and that the rejection is caused by factors other than antibodies, such as platelet activation.
B-cell activation and regulation occur via several mechanisms that are T-cell dependent or independent. B-cell responses against MHC antigens are T-cell dependent and require the involvement of antigen-presenting cells and costimulatory molecules such as CD40 ligand or soluble interleukins. These responses take two to three weeks to develop and lead to immunologic memory, allowing a more effi cient antibody response upon repeat stimulation.
Denis F. COMPREHENSIVE PEDIATRIC NEPHROLOGY. ISBN: 978-0-323-04883-5.2008
· CD4+ T cells are one of the most important components of rejection process .They include Th1, Th2 and recently recognized Th-17. Treg, Tfh and TH9 are other subsets with different functions.
· Th1 cells secret IFN-γ and IL-2 that have different function in activation of CD8+Tcells, macrophages and B cells and then complement system. They express Fas ligand and cytotoxic activities.
· On contrary IFN- γ can induce T regs and inhibit Th 17 cells.
· Th2 cells secret different interleukins (4, 5, 9, 10 and 13) which can activate B cells and induce eosinophil infiltration .They have a special factor named GATA-3. IL-9 is active in allergy and its role in rejection should be determined.
· Th17can recruit neutrophils to graft by secreting IL-17, IL21 and IL-22, IL-17 is more important in acute rejection than chronic form.
· Cytokines induce transition of T lymphocytes to memory Tcells (TM)
· Tregs or regulatory Tcells are important to induce tolerance by expression of CD25 or secretion of IL-10 and TGF β.
Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol. 2010 Jan;6(1):155-69.
naive CD4 T cell needs Ag recognition to be activated by direct and indirect bath ways .
After CD4 T cell recognition, 3 signals leads to its activation:
Signal 1/ TCR CD4 and Ag on ApC
Signal 2/CD80/86 on APC and CD23 on T cell
Signal 3/CD4Tcellproliferation and differentiation into effector cells which include:
Th1 secret inflammatory cytokines and aggravate immune system.
Th2 secret inflammatory cytokines and inhibit immune system
Th17 aggravate immune system
Tfh start humoral immune response
T memory it’s life long resistant to treatment.
It induce tolerance by the aid of Treg.
The ability of recipient T cells to recognize donor-derived antigens, called allorecognition, initiates allograft rejection. Once recipient T cells become activated, they undergo clonal expansion, differentiate into effector cells, and migrate into the graft where they promote tissue destruction. In addition, CD4 T cells help B cells produce alloantibodies. The Naïve CD4+ T helper cells (nTh) are one of the first immune cells to be activated post-transplant, playing a key role in the rejection. Activated nTh develop into either Th1 (pro-inflammatory) or Th2 (anti-inflammatory) subtypes. Each subtype orchestrates a characteristic, immune response profile.
In the presence of TGF-β and IL-6, nTh differentiate into Th17 cells, a novel subset of Th cells that secrete IL-17 whose role in transplant immunology is still unclear. However, it appears that Th17 cells together with Th1 and Th2 cells play an important role in mediating allograft rejection. A Th1 response is correlated with acute rejection episodes with the production of pro-inflammatory cytokines – IFNγ, IL-2, IL-12, TNFα and GM-CSF. This cytokine profile activates macrophages, natural killer (NK) cells and cytotoxic T cells (Tc) which are drawn to the graft and activate caspases that induce cell apoptosis.
Memory CD4+ T cells not only become effector cells upon reactivation but also provide help for the robust activation of donor-reactive effector CD8+ T cells. These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival. Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft. Once in the graft parenchyma, these memory CD8+ T cells proliferate extensively, upregulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
Influence of Memory T Cells on Allograft ToleranceEven though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances, they demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses. Krupnick et al. have reported that early infiltration of central memory CD8+ T cells is essential for lung allograft acceptance after treatment with CTLA4-Ig and anti-CD154 mAbs. Similarly, CD8+CD45RClo cells with regulatory properties have been described in rat models of solid organ transplantation and GVHD.
References:
1. Liu Z, Fan H, Jiang S. CD4(+) T-cell subsets in transplantation. Immunol Rev. 2013 Mar;252(1):183-91.
2. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010 Jan;25(1):61-74.
3. Benichou G, Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology. 2017 Feb 28;8:170.
What is the role of T helper cells (CD4) in
Graft damage with emphasis on acute cellular and antibody mediated rejection.
There is two main types of Tcells Cd4(helper) which interact with antigen presented by APC on HLA class 2
Cd8(cytotoxic) which interact with antigen presented on HLA class 1
Naive Cd4Tcell needs antigen recognition to be activated (adaptive) by 3 main pathways
Direct: by donor APC (100folds potent)
indirect:by antigenic part presented by recipient APC
Semidirect: by whole donor HLA presented by recipient APC
After Cd4Tcell recognition it’s activation started by 3signals
Signal 1: connection between TCR Cd4 and antigen presented on APC
signal 2: connection between cd80/86 on APC and Cd28 on t cell
Signal 3: Cd4Tcell proliferation under effect of IL 2on Cd25 and differentiate into effector t cells which includes
Th1: secrets IL2 and interferone gamma and other inflammatory cytokines and aggravated immune system
Th2: secrets IL10 and antiinflammatories cytokines and inhibit immune response
Th17: secrets IL17 and aggravates immune response
Tfh: which introduce antigen to bcell in the 2ry lymphoid organs and starts humoral immune response
Tmemory: which life longer and get activated without signal 2 and resistant to treatment.
What is the role of T helper cells (CD4)in Induction of tolerance
One of the effector Cd4Tcell is T-regulatory
Treg: which also includes subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy
Its stimulate tolerance by 2main mechanisms
1) contact dependent:it express cd25 on its surface and interact with conventional t cell on signal 2 stimulation and induce anergy
2)non contact dependent: it secrets IL10 and TGF beta which influence inhibitory effect on adaptive immune system.
Also treg affected by immunosuppressant medications as below
Cni decrease number and function of Treg by inhibition of IL2 secretion
ATG depleting both conventional and treg but treg regenerate faster
Alemutzumab affect conventional tcell more than treg and elicit more tolerance.
MTOR,MMF and steroids increase treg expression and activity.
Reference:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169
2) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336
After activation of T lymphocytes by cytokines that produced by APCs it will be proliferate and differentiate into 4 major helper cells (Th1,Th2,Th17,Tfh)and one regulatory subgroup, CD+ T cells can be cytotoxic.
Th1 lymphocyte: this type is responsible for graft rejection by producing cytokines leading to macrophages activation and depend on IL-2 and interferon gamma for their proliferation.
Th2 lymphocytes :IL4 and transcription factors STAT6 and GATA3 are responsible for their differentiation ,they are responsible on allergic reaction also activation of eosinophils, basophils and mast cells ,Th2 lymphocytes inhibit Th1 lymphocyte in delay rejection .
Th17 lymphocytes: produced by IL-6 and transforming growth factor B ,and they are developed in early stage of immune reaction also cause inflammatory response to bacterial infection, they have ability to produce IL-17
Tfh lymphocytes : their proliferation depen on IL-21 and on the transcription factor Bc16 ,they play role in differentiation of activated B cells to Ab producing plasma cells also they contribute in alloantibodies production that affect on graft survival.
THE helper T lymphocyte orchestrates the adaptive immune system . These cells can secret cytokines and activates B cells to become plasma cells . Many subtypes of T helper lymphocytes:
TH1 Lymphocytes : secrets interferon and TNFa which can lead to graft damage directly, also it activate macrophages, stimulate Cytotoxic T lymphocytes, stimulate the differentiation of B cells into immunoglobulin producing plasma cells.
TH2 Lymphocytes : secret cytokines Iike IL4, IL5 , IL10 which activates mast cells and basophiles . TH2 can suppress TH1 lymphocytes.
TH17 Lymphocytes : secretes IL17, which leads to attraction of inflammatory cells to the graft.
Tfh Lymphocytes: T follicular helper lymphocytes stimulate B cell to differentiate to plasma cells through CD40- CD40L and produce IL4, IL21.
Once helper T cells activated By direct or indirect pathway , they start to proliferate and migrate to the graft and secrete cytokins that activate cytotoxic T cells and NK cells and macrophages also secrete interferon that leads to graft damage and cellular mediated rejection.
T regulatory Lymphocytes (Fox3 +): These cells can suppress T helper and T cytotoxic Lymphocytes and can induce tolerance to the graft .
CD4+ T helper cells are one of main cells playing a key role in rejection.
Activated CD4 T cells develop into either Th1 (pro-inflammatory) or Th2 (anti-inflammatory) subtypes.
Each subtype leads to a characteristic, immune response profile .
In the presence of certain cytokines
T helper cells differentiate into Th17 cells, a novel subset of Th cells that secrete IL-17 whose role in transplant immunology is still unclear.
*In case of cellular rejection, activation of t helper cells eventually causes production of pro-inflammatory cytokines – IFNγ, IL-2, IL-12, TNFα and GM-CSF.
This cytokine profile activates macrophages, natural killer (NK) cells and cytotoxic T cells (Tc) which are drawn to the graft causing its destruction
Th2 cells result in the activation of B cells.
B cells express MHC class II, which present to Th2 cells (indirect), resulting in Th2 activation/proliferation.
The resultant Th2 cells are specific for B cell and secrete IL-2 for B-cell proliferation and IL-4 and -5 for antibody class switching.
activated B cells differentiate into plasma cells which secrets antibodies (mainly IgG and IgM) with specificity towards the graft.
Interaction of Ab with the graft endothelium eventually leads to the activation of complement, and cell destruction
B cells develop into memory cells and developing an immunological memory towards the graft.
T regs which is a subset of t helper cells ,inhibits deleterious immune response of T helper cells on self antigens thus promoting tolerance to transplanted organ.
An important discovery in the field of Treg therapy in humans is the finding that Tregs can be isolated and expanded in vitro while maintaining immunoregulatory function.
Studies showed that infusion of Tregs has the potential to induce long-term donor-specific tolerance without interfering with immune responses to pathogens and tumors in transplant patients.
T helper
helper T cells are a CD4 cells that can differentiate into several different subtypes, including Th1, Th2, Th3, Th17, T reg and T f h . Each subtypes secretes a different panel of cytokines that can drive the immune response in a specific direction, so these CD4+T helper cells play a vital role in various immunologic processes as activation of cytotoxic T cells and APCs , maturation and differiation of B cells into plasma cells and memory B cells , antibody production by B cells, recruitment of various inflammatory cells PMNs, eosinophils and basophils as well as development of tolerance and suppression of immune responses
T lymphocyte recognize the non self HLA Ags on the transplanted graft , after their presentation on either donor APC (direct allorecognition pathway) or on recipient APCs after processing these Ags . This is followed by priming of both CD4+ and CD8+ T lymphocytes .The activated T helper cells stimulate differitaion of B lymphocytes into Ab producing plasma cells via IL 21 production which may induce graft injury , T helper cells are also important for the survival of memory B cells . In their study , de Graav, G and his collegues found increased number of follicular T helper cells in association with B cells infilterating the graft during rejection and the level of follicular t cells were positively correlated with pretransplantation DSA level which indicates the role of both B and T helper cells in graft rejection . (1)
1- de Graav, G. N., Dieterich, M., Hesselink, D. A., Boer, K., Clahsen-van Groningen, M. C., Kraaijeveld, R., Litjens, N. H., Bouamar, R., Vanderlocht, J., Tilanus, M., Houba, I., Boonstra, A., Roelen, D. L., Claas, F. H., Betjes, M. G., Weimar, W., & Baan, C. C. (2015). Follicular T helper cells and humora
The role of T helper cells (CD4) in the following?
In cellular rejection
T cells cause allograft rejection either by eliciting a DTH (delayed-type hypersensitivity) response or through cytolytic/cytotoxic activity . DTH responses are primarily mediated by alloantigen-specific CD4+ Th1 cells, which secrete IFNg(gamma) and TNF-a(alpha). These
proinflammatory cytokines activate monocytes and macrophages which, in turn, cause nonspecific tissue injury through the release of proteolytic enzymes, nitric oxide, and other soluble factors. These factors affect vascular tone and permeability, in addition to promoting chemotaxis and further activation and differentiation of antigen-specific T cells
In antibody mediated rejection
T- helper is important for maturation of B- cells and enhancing its proliferation and production of antibodies
In healthy individuals, immune homeostasis is maintained through a balance between effector and regulatory cells of either T or B cell lineage. Of these, CD4+CD25+FoxP3+ regulatory T
cells (Treg) have received the most attention as targets for inducing peripheral tolerance.
Treg in humans are CD4+ T lymphocytes that express high levels of CD25 and the transcription factor Foxp3. Anergy and exhaustion refer to the state in which T or B lymphocytes become unresponsive to re-stimulation with antigen. tolerant transplant patients show a suppressed DTH response to donor antigens
CD4 had four major helper subpopulation:
1-Th1:produced by dentritic cells,they activate macrophages by produce lymphotxin,INF gama and TNF alfa which lead to damage of graft endothelial cells and stimulate CD8 T lymphocytes to CTL.
2-Th2: responsible for allergic reaction,activated by lL-4 lead to production of eosinophils,basophils and mast cells,it can lead also to antibody production.some times inhibit Th1 formation and delay rejection.
3-Th17: responsible for responding to fungal infections,contribute to allograft rejection by promoting inflammation,also can lead to formation of tertiary lymphoid tissue at the sites of chronic inflammation which share similar architecture to lymph nodes which observed in allograft with chronic rejection.
4-Tfh(follicular helper): help B lymphocytes to produce antibodies via CD40l -CD40 interaction, it is beneficial by blocking T-lymphocytes activation
T-cell phenotypes
Activation of naive CD4+ T cells results in T-cell maturation and differentiation to phenotypes with effector functions.
CD4+ T helper lymphocytes play an essential role in adaptive immunity and in inducing immune response.
They are involved in both AMR and CMR.
CD4+ T cells can differentiate from pluripotent naive cells (Thp) into at least four types , Th1, Th2, Th17, and regulatory T cells (Treg) 1.
Th1 cells are the proinflammatory T cell, play central role in delayed-type hypersensitivity responses and the response to intracellular pathogens such as Mycobacteria sp. many studies of transplant rejection have concentrated predominantly on Th1 responses and IFN-γ production( which is also produced by other cells ) 2.
T-bet, the signature transcription facture of Th1 cells, can be identified in renal transplant biopsys during of acute rejection, similar to IFN-γ, T-bet is pleiotropic and also expressed by many other cell types including DCs and natural killer cells and therefore not specific to Th1 cells during rejection 3.
interferon gamma and IL-2 leading to CD8+ cytotoxicity, macrophage dependent delayed type hypersensitivity and IgG2 synthesis from B cells stimulating complement leading to rejection.These are mainly responsible for cell-mediated immunity.
Th17 cells produce the highly proinflammatory cytokine, IL-17, and are central to the response to extracellular pathogens.
Th17 is strongly association with autoimmune diseases and are now considered principal mediators of human autoimmune diseases 4.
In the transplant setting, an elevation in IL-17 mRNA in rejecting rat renal allografts and IL-17 protein in infiltrating mononuclear cells can be seen as early as day 2 after transplantation
IL-17 protein is elevated in human renal allografts during subclinical rejection, together with detectable IL-17 mRNA in urinary sediments 5.
Follicular T helper cells are CD127- , provide help for activated B lymphocytes leading to plasma cell derived antibodies.
Tregs
Tregs, specifically CD4+ T cells expressing high levels of CD25 (the IL-2 receptor α-chain) and the transcription factor (FOXP3),are derived by thymic selection of cells with higher affinity for self-MHC (natural or ‘n’Tregs) and also from the periphery during immune activation in the presence of TGF-β and/or retinoic acid (inducible or ‘i’Tregs).
Tregs have potent suppressive function and
important in maintenance of tolerance to self-antigens, preventing development of autoimmune diseases 6.
Tregs don’t have significan effect in the early posttransplantion period but greater impact on modifying chronic rejection. Indeed, emerging data show that Treg numbers present in human protocol renal transplant biopsies showing borderline or acute cellular rejection at 1 year correlate inversely with better creatinine and less interstitial inflammation.
the presence of high numbers of Tregs (measured using the surrogate marker of FOXP3/CD3 ratio) in renal biopsy specimens containing inflamed fibrosis correlates with better allograft survival 7.
Tregs may also have an impact on humoral alloresponses, which are of relevance in chronic rejection. a tolerizing protocol, involving pretransplant treatment of recipients with anti-CD4 monoclonal antibody plus donor-specific transfusion, resulted in the induction of CD4+ Treg cells, which prevented the generation of alloantibody and graft rejection.
Tolerance induction in this model was actively dependent on the continued presence of Tregs and could be reversed with depletion of these cells 8.
Two broad possibilities for Treg therapy exist in humans,one is by induction of Tregs from naive precursors in vivo using targeted delivery of alloantigen under tolerizing conditions and the other is by infusion of autologous Tregs expanded from peripheral blood ex vivo
1 McGeachy, D.J. Cua
Th17 cell differentiation: the long and winding roadImmunity, 28 (2008), pp. 445-453
2 Alcaide, T.G. Jones, G.M. Lord, et al.
Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue
J Exp Med, 204 (2007), pp. 431-439
3 Sawitzki, C.I. Kingsley, V. Oliveira, et al.
IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo
J Exp Med, 201 (2005), pp. 1925-1935.
4 Afzali, G. Lombardi, R.I. Lechler, G.M. Lord
The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease Clin Exp Immunol, 148 (2007), pp. 32-46.
5 Loong, H.G. Hsieh, W.Y. Lui, et al.
Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection
J Pathol, 197 (2002), pp. 322-332.
6 H.D. Ochs, E. Gambineri, T.R. Torgerson
IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity .9immunol Res, 38 (2007), pp. 112-121.
7 Taflin, D. Nochy, G. Hill, et al.
Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft functionTransplantation, 89 (2010), pp. 194-199.
8 C.J. Callaghan, F.J. Rouhani, M.C. Negus, et al.
Abrogation of antibody-mediated allograft rejection by regulatory CD4 T cells with indirect allospecificity
J Immunol, 178 (2007), pp. 2221-2228.
CD4+ T lymphocyte differentiate into major helper subgroups with effector activities (Th1, Th2, Th9, Th17, Th22, and follicular helper T cells [Tfh]) and those with regulatory activities (natural regulatory T cell [nTreg], induced regulatory T cell [iTreg (type 1 regulatory T cell [Tr1])], Th3). CD4+ T lymphocytes can also be cytotoxic.
All effector T-lymphocyte subsets participate in allograft rejection, although some of them play a more dominant role than others.
Th1 lymphocytes are the prototype of lymphocytes responsible for rejection. Their differentiation is driven by IL-12 and INFγ. The transcription factors STAT1 and T-bet are necessary for their differentiation.Th1 lymphocytes produce large amounts of INFγ, TNFα and lymphotoxin which promote allograft rejection by activating macrophages, direct damage on graft endothelial cells, inducing production of complement-fixing IgG antibodies by B lymphocytes, and stimulating the differentiation of CD8+ T lymphocytes to CTL (cytotoxic T lymphocytes)
Th2 lymphocytes are the lymphocytic subset responsible for allergic reactions. They also contribute to allograft rejection. Their differentiation depends on IL-4 and transcription factors STAT6 and GATA3. They produce IL-4, IL-5, IL-9, IL-10, and IL-13, which activate eosinophils, basophils and mast cells and usually enhance the production of not complement fixing antibodies. IL-10 also has immunoregulatory properties that prevent rejection. The role of Th2 lymphocytes in mediating rejection is less potent than Th1 lymphocytes and may inhibit Th1 formation and delay rejection, so they have a dual role in kidney transplantation.
Differentiation to the Th17 phenotype depends on TGFβ, IL-6, and IL-21 and on the transcription factors STAT6 and RORγT.Th17 lymphocytes produce IL-17, and contribute to allograft rejection via inducing inflammation. IL-17 stimulates the production of neutrophil chemoattractants by epithelial and other stromal cells in the graft. Th17 lymphocytes also participate in the formation of tertiary lymphoid tissues at sites of chronic inflammation which have been observed in renal allografts undergoing chronic rejection that suggests their participation in the local immune response.
Th9 lymphocytes that produce IL-9, are involved in either immunity or tolerance.
Tfh (follicular helper lymphocytes) play a key role in high affinity antibody production by providing help to B lymphocytes. Their generation is dependent on IL-21 and on the transcription factor Bcl6. They induce the differentiation of activated B lymphocytes to antibody producing plasma cells. Engagement of CD4 on B lymphocytes by CD 154 on CD4+ T lymphocytes is an important mechanism by which CD4+ T lymphocytes provide help to B lymphocytes for IgG production.
Secretion of cytokines, namely IL-4 and IL-21, are essential for this differentiation as well. Thus, Tfh lymphocytes are important for driving the production of alloantibodies that are detrimental to graft survival. In the presence of appropriate cytokines and B cell interactions, Tfh cells can differentiate into Th1-like, Th2-like, or Th17-like Tfh cells.
Treg cells typically comprise 1 to 2 percent of the total CD4 population, but overall are critically responsible for the suppression of effector CD4 T cell effects through contact inhibition of activity between APC and effector T cells or direct cytotoxicity.
CD4+ T cells have an important role in alloresponse.
They are very much involved in graft damage by both cell-mediated immunity and antibody-mediated immunity.
The various subsets of CD4+ T cells include: (1)
1) Th1 cells: These secrete interferon gamma and IL-2 leading to CD8+ cytotoxicity, macrophage dependent delayed type hypersensitivity and IgG2 synthesis from B cells stimulating complement leading to rejection. They also have FasL which leads to cytotoxicity. These are mainly responsible for cell-mediated immunity.
2) Th2 cells: These have role in humoral immunity. They secrete IL 4,5,9,10 and 13, activating B cells and eosinophils leading to chronic graft rejection.
3) Th17 cells: these secrete IL17, 21 and 22 leading to recruitment of neutrophils at rejection site. These have role in acute rejection in early post transplant phase .
4) Tfh: Follicular T helper cells are CD127- , provide help for activated B lymphocytes leading to plasma cell derived antibodies.
5) Treg (regulatory T cells): These suppress potentially deleterious actions of the Th cells. (2) These have role in immune tolerance.
Reference:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169
2) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336.
CD4+ cells are T-helper cells that have CD4 markers on their surface.
CD4+ T helper lymphocytes play an essential role in adaptive immunity and play an important role in establishing and maximizing the immune response. These cells have no cytotoxic or phagocytic activity, and cannot kill infected cells or clear pathogens. However, they mediate the immune response by directing other cells to perform these tasks. Th cells are activated through TCR recognition of antigen bound to class II MHC molecules.
once CD4+ T cell recognize foreign antigens on MHC class II , they become activated ,
Once T cell activation occurs, a chain of intracellular events is triggered under the influence of a variety of growth factors as IL-2 with expression of cell surface molecules and production of cytokines which lead to
1. stimulation of monocytes that play an important role in destruction of graft .
2 . stimulate the activation and proliferation of cytotoxic CD8 T cells and natural killer cells ( achieve cellular inflammatory responses) .
3 .stimulation of B cells with proliferation and differentiation into plasma cells . plasma cells release soluble immunoglobulins or antibodies which can bind allogeneic cells.
Antibodies can cause cell damage by fixing of complement or by mediating antibody dependent cellular cytotoxicity (humoral immune response).
They are a special subpopulation of CD4 cells.
Type 1 helper T cells (Th1) cells produce interleukin-2 (IL-2) and interferon-gamma (IFN-g) and induce macrophage activation, leading to delayed-type hypersensitivity responses. Acute allograft rejection is predominantly mediated by a Th1 immune response.
Type 2 helper T cells (Th2) cells produce interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), and interleukin-13 (IL-13), and provide help for B-cell function . IL-4 is a growth factor for B cells and antibody production and also can directly inhibit T cell maturation into the Th1 pathway.This act against parasitic (predominantly helminthic) infections in mammals.A switch from a Th1 to a Th2 cytokine expression is associated with allograft tolerance .
Type 17 helper T cells( Th17) cells are a T cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance.
regulatory T (Treg) cells limit and suppress the immune system and, thereby, may function to control aberrant immune responses to self-antigens and the development of autoimmune disease.
References
Santarlasci V, Cosmi L, Maggi L, Liotta F and Annunziato F : IL-1 and T helper immune responses. Front. Immunol.2013: 4:182.
Hand book of kidney transplantation by G.M.Danovitch,fifth edition.
UpTo Date
Well done Alia you have a clear grasp of the helper Tcells, waiting for the Tregs.
T helper cells (CD4)
T helper cells (CD4) & induction of tolerance
T follicle helper cells (Tfh cells) are a specialized subset of CD4+ T cells. Yuhong et al reported a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5.
(Chen, Yuhong, et al. “CXCR5+ PD-1+ follicular helper CD8 T cells control B cell tolerance.” Nature communications 10.1 (2019): 1-15.)
https://www.nature.com/articles/s41467-019-12446-5
Upon activation of naive CD4+helper T (Th) cells by antigen-presenting cells, it differentiate into different Th cell subsets, Th1, Th2and Th17, with different cytokines and effector functions This is promoted by the IFN-c-induced activation of STAT-1 and T-bet, the Th1specific transcription factor. T-bet promotes Th1 lineage and forms positive feedback loop with IFN-c.
On the other side IL-4 induces differentiation of Th2, engagement of IL-4 receptor leads to the phosphorylation of STAT-6which binds to the IL-4 promoter and inducesIL-4 production, thus forming a positive feedback
loop to increase Th2 differentiation. Several authors published that prevalence of Th1 over Th2 is specific to acute renal allograft rejection .
Th17expresses a transcription factor different from those of Th1 and Th2
cells, the retinoic acid-related orphan receptor ct (RORct) The combination of the IL-6with TGF-b induces the differentiation of Th17cells producing large quantities of IL-17. (1)
Antigens nature and graft type affects mechanisms of allograft rejection. T lymphocytes can injure allografts of dispersed cells by direct effector mechanisms also can act indirectly through secreted cytokines which can themselves directly injure target cells or through effects of cytokines on macrophages. Renal allograft can be rejected through effects on blood vessels rather than injury to the parenchymal cells (2)
CD4+ cells recognize class II MHC molecules on the donor tissue (HLA-DP, HLA-DQ, HLA-DR), and are induced to secrete interleukin-2 (IL-2), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), which activate CD8+ cells, NK cells, and macrophages. The Th1 CD4+ cells also give signals to activate the Th2 CD4+ group to secrete the cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-10 (IL-10), which can activate B cells and immunoglobulin production.(3)
Some T cells can be demonstrated to downregulate other T cell and/or B cell responses, referred to as T-suppressor cells,known as regulatory T cells (T-regs). There are two basic types of T-regs; tTregs that are produced in the thymus and are involved in controlling autoimmune disease; and iTregs that are induced during immune responses and are terminating immune responses .T-reg cells help maintain the balance between protection and an immune-mediated injury .(4)
Chimeric antigen receptor (CAR) T cell therapy in the induction of graft tolerance by immune cells been limited to the laboratory. Recently, innovative CAR-Treg therapies in animal transplant models was demonstrated CAR-Tregs genetically modified with coding CARs are non-MHC dependent and have better antigen specificity. The mechanism of CAR-Tregs targeting specific tissue sites and successfully reduced GVHD in the mouse model .The mAb-CAR-Tregs targeted MHC class I proteins on allografts and prolonged it’s survival .(5)
1- Loverre A etal. T helper 1, 2 and 17 cell subsets in renal transplant patients
with delayed graft function. Transplant International 2010 , 24 (2011) 233–242
2- Frank W. Fitch, Cell Medicated Immunity .Encyclopedia of Immunology (Second Edition), 1998
3- Jeffrey K. Actor, Transplantation Immunology. Introductory Immunology (Second Edition), 2019
4- Burrell C Jet al , Adaptive Immune Responses to Infection.Fenner and White’s Medical Virology (Fifth Edition), 2017
5-Gan X etal . Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance. Engineering 7 (2021)
Dear All
I’m impressed with your contribution. We are nearly there where we will be finishing the discussion of basic immunology soon.
One last question regarding helper T cells
What subtype favours rejection and graft damage and which subtype favours tolerance?
Th1 favours rejection and graft damage ( it is pro inflammatory and secrete pro inflammatory cytokines), Th2 favours tolerance as it is antiinflammatory
Well done, yes you are right
I think all the Th-cells with subtypes that promote the expression or activiation of proinflammatory cytokines and chemtokines like Th1, Th2, Th9, Th17, Th22, Thf all can lead to rejectionand graft damage while the Th-cells with subtypes promote the immunesuppressive and immune modulation effect can help with tolerance induction like Treg , iTerg anf Th3 cells
Thanks Saja for your reply
See Riham answer above.
To add more confusion, even Th2 may be also involved in rejection also. The immune system is very complicated.
Th1 subtype of naive CD4+ T cells is pro-inflammatory, while Th2 subtype is antiinflammatory. Hence Th1 has role in acute rejection and graft damage.
Th2 is antiinflammatory, hence has role in tolerance. But it also has role in chronic rejection by secretion of IL-4,5,9,10 and 13 activating B cells and eosinophils promoting chronic rejection.
Th1 involve in rejection
Th2 involve in both tolerance and rejection
Th1 responsible for rejection and Th2 inhibit Th1 formation so they lead to immune tolerance
Th1 is proinflammatory cells secrets INF gama, IL-2 which activate CD8 + cytotoxic cells macrophages, & production go IgG2 by Cells that activate complement lead graft rejection.
Th2: produce IL-4, IL-10 & Il-13, these cytokines will activate B cells & induce chronic rejection.
Although TH2 also may induce tolerance and have som anti-inflammatory action
Th1, Th17, and Thf favour rejection, Th2 and Th9 may have dual role and are involved in either immunity or tolerance.
Generally TH1 involved in rejection and graft damage, while TH2 may take part induction of tolerance. Interestingly TH2 may provide B cells help including immunoglobulin class switching.
Traditionally, T cells were CD41 helper or CD81 cytotoxic T cells, and with antibodies, they were the soldiers of immunity. Now, many functionally distinct subsets of activated CD41 and CD81 T cells have been described, each with distinct cytokine and transcription factor expression.
1-CD41 T cells, these include Th1 cells expressing the transcription factor T-bet and cytokines IL-2, IFN-g, and TNF-b
2-Th2 cells expressing GATA-3 and the cytokines IL-4, IL-5, and IL-13
3-Th17 cells expressing RORgt and cytokines IL-17A, IL-17F, IL-21, and IL-22.
The cytokines produced determine the immune inflammation that they mediate
T regulatory cells or spies were characterized as CD81 T cells expressing I-J in the 1970s.
In the 1980s, suppressor cells fell into disrepute when the gene for I-J was not present in the mouse MHC I region. At that time, a CD41 T cell expressing CD25, the IL-2 receptor-a, was identified to transfer transplant tolerance. This was the same phenotype of activated CD41CD251 T cells that mediated rejection. Thus, the cells that could induce tolerance and undermine rejection had similar badges and uniforms as the cells effecting rejection.
Clin J Am Soc Nephrol 10: 2050–2064, 2015. doi: 10.2215/CJN.06620714
Th lymphocytes are the most important cells in adaptive immunity, as it is necessary for all adaptive immune responses.It activate B cells, macrophages & cytotoxic T cells. Naive T cells are activated through TCR when interact with MHCII in presence of co stimulatory molecules on APC.Th cells is the first immune cell that activated post transplantation. There are several subtypes of Th cells:
References;
What is the role of T helper cells (CD4) in the following?
-CD4+ T cells were functionally and phenotypically heterogeneous and capable of cross talk.
-CD4 T cells mediated delayed type hypersensitivity response (DTH) is sufficient to cause rejection without the need of cytolytic function of CD8 cells ,upon activation of CD4 produce subsets of cytokines to regulate the immune response which is antigen dependent stimulation.Activated APCs deliver three types of signals required for the clonal expansion and maturation of CD4+ T cells ,the first signal is mediated by the peptide-MHC interaction with the TCR,while the second involves costimulatory interactions between the APC and the T cell. The third signal directs differentiation of naive T cells to effector T cell subsets
-CD4 can further differentiated to subsets of cells:
-Type1Th cells secret cytokines like IL2,IL12 , INFγ, and TNF.
-Type2 Th cells secret cytokines like IL4,IL5,IL10 and 13 .
Its thoughts that Th1 activation can lead to rejection of the graft as type 1 cytokines promote effector functions such as DTH and cytolytic activity, promot cell mediated immunity ,enhance clearnce of intercellular pathogens and tumor cells ,opsonsing the AB production by B cells.
while Th2 responses might induce tolerance of the graft as the type 2 cytokines
antagonize the effectors and cytolytic activity, few studies shows that graft rejection associated with production of type1 and 2 cytokines while tolerance induced by inhibition of both types of cytokines.
-Th17 which produce cytokine 1L17 which have strong inflammatory effect that’s why the Th17 cells considered target for anti-rejection therapies .
-Th9 producing cells are proinflammatory as they stimulate proliferation and inhibit apoptosis of hematopoietic cells and also activate Th17 cells, -Th9, Th22, and IL-25 maintained mucosal immunity .
References :
1- hand book of kidney transplantion , Fifth-edithion Gabriel M.Danovitch
2-Review Article Functional and Phenotypic Plasticity of CD4+ T Cell Subsets
BioMed Research International Volume 2015, Article ID 521957, 13 pages http://dx.doi.org/10.1155/2015/521957.
there are different types of T helper cells:
Type 1 —
release IL2 and IFN gamma – responsible of acute graft rejection through macrophage activation.
Type 2 —
Release interleukins 4,5,10 and 13. it promotes B cell function through IL4. TH2 is concerned with graft tolerance.
Type 17 —
Associated with graft rejection with a still to be completely understood mechanism. theories are Th17 increase cytokines e.g FGF, TGF-1. also, cyclosporine may increase cytokines and thus leads to allograft fibrosis.
Ref:
Uptodate.com Accessed 23/11/2021
T lymphocytes are differentiated into multiple effector populations by cytokines that are either produced by antigen-presenting cells or activated T lymphocytes. CD4+ T lymphocytes differentiate into 4 major helper subsets and one regulatory subset, whereas CD8+ t lymphocytes differentiate into cytotoxic T cells.
T helper lymphocytes :
T helper lymphocytes are the most important cell in adaptive immunity. Ther are classified into:
Th 1 lymphocytes :
– Their differentiation depends on IL-12 and interferon-gamma also transcription factors STAT 1 and T-bet are necessary for their differentiation.
-They produce TNFα and lymphotoxin which activate macrophages and lead to allograft rejection.
-Ustekinumab, a monoclonal antibody against IL-12, was used in the treatment of psoriasis but not tested in transplantation.
Th 2 lymphocytes:
– Their differentiation depends on IL-4 and transcription factors STAT6 and GATA3.
-They produce IL-4, IL-5, IL-9, IL-10, and IL-13, which activate eosinophil and basophil and mast cells and enhance the production of particular antibody isotypes.
-It is responsible for allergic reactions while IL-10 can dampen rejection.
-It inhibits Th 1 lymphocytes formation and delay rejection
Th 17 lymphocytes :
– Their differention depends on TGFβ, IL-6, IL-21, and transcription factors STAT6 and RORɣT.
-It promotes inflammation by the production of IL-17. They respond to fungal infections.
They participate in the formation of tertiary lymphoid tissue at the site of chronic inflammation which is observed in renal allograft undergoing chronic rejection.
T FH (Follicular helper)lymphocyte
-Their differention depends on IL-21 and transcription factors Bcl6.
-They provide help to B lymphocytes for antibodies production and drive alloantibodies which are determintal for graft survival.
Th 9 lymphocyte :
– Their differention depends on IL-4 and TGFβ.
-They produce IL-9.
-It involves either immunity or tolerance.
Treg FoxP3:
-Regulatory T cells (Treg )are a specialized subpopulation of T cells that act to suppress the immune response.
-It can inhibit T cells proliferation, cytokine production by T cells, and suppress B cells and dendritic cells.
– The most specific marker for these cells is FoxP3, which is localized intracellularly.
References
1. Danovitch G.M handbook of kidney transplantation sixth edition
2.Veldhoen, Marc; Uyttenhove, Catherine; van Snick, Jacques; Helmby, Helena; Westendorf, Astrid; Buer, Jan; Martin, Bruno; Wilhelm, Christoph; Stockinger, Brigitta (December 2008). “Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset”. Nature Immunology. 9 (12): 1341–1346. doi:10.1038/ni.1659. ISSN 1529-2916. PMID 18931678. S2CID 205361860.
Th are the key orchestrators of adaptive immunity , once activated they differentiate into a variety of effector cells that secrete various cytokines which can cause graft injury or induce tolerance.
The pattern of cytokine production defines the subset of T helper cells.
T lymphocytes populations and functions:
T helper (Th)1, Th2, Th9 and Th17 cells promote acute allograft rejection
regulatory T cells that are required to maintain self-tolerance
follicular helper T cells (TFH) that provide help to B cells for antibody production
TH1:responsible for graft rejection
Produces IFN-y, TNF alpha that activate macrophages, activate B lymphocytes that produce complement fixing IgG AB and stimulate differentiation of CD8 T cells to cytotoxic T cells
TH2: responsible for allergic reactions. They secrete IL-4 and IL-10 (and other cytokines) and help antigen-primed B lymphocytes differentiate into plasma cells and secrete antibodies, the effector molecules of humoral responses. (less potent than TH1)
TH9:They play a role in the immune response against tumor cells, allergy, and autoimmune disease
TH17: produce IL17 that can cause graft rejection by promoting inflammation and formation of tertiary lymphoid tissue at the inflammation site
Tfh (follicular): provide help for activated B lymphocyte to differentiate to AB producing plasma cells .
Memory T lymphocytes: few effector lymphocytes give rise to memory T cells which have longer life span, wider migration pattern, lower threshold for activation than naïve T cells with a stronger immune response that is partially responsive to co-stimulatory pathways as B7-CD28
Regulatory T cells (Tregs): usually secrete IL-10 and TGF beta (TGF β).They are specialized subpopulation of T cells that inhibit T cell proliferation cytokine production, preventing autoimmunity and down-regulate the allo-immune response
.
Tregs produce immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, that modulate APC functions, and can contribute to T effector cells suppression. So simply they are in charge of suppressing potentially deleterious activities of Th cells.
We conclude that the stimulatory activities of T cells in inducing allograft injury need to be counterbalanced by suppressive mechanisms, in order to fine-tune the immune responses and induce tolerance.
Mechanism of cellular rejection in transplantation. Elizabeth Ingulli. Pediatr Nephrol. 2010; 25(1): 61–74
Plasticity of human CD4 T cell subsets. Jens Geginat et al. Front. Immunol., 16 December 2014
Hand book of renal transplantation, sixth edition
Immunopedia.og. overview of T cell subsets.
CD4+ T-helper cells play an important role in alloimmune reactions the following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA.
Consequently, the reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcomes.
CD4+ T-helper cells are of significant importance during allograft rejection. During T-cell-mediated rejection, these cells are likely able to stimulate intermediary antigen-presenting cells, which can consequently prime CD8+ cytotoxic T-cells.
In the formation of HLA antibodies, CD4+ T-helper cells can stimulate B-cell proliferation and differentiation. More specifically, CD4+ T-helper cells may recognize epitopes derived from mismatched HLA via the indirect pathway of allorecognition.
In this process of indirect allorecognition, mismatched HLA molecules are internalized and processed into peptide fragments by antigen-presenting cells such as B cells.
These HLA-derived peptides are subsequently presented on the cell surface of these antigen-presenting cells by HLA class II molecules. The CD4+ T-helper cells, in turn, recognize these allopeptide-HLA class II complexes and provide help to naive B cells by stimulating B-cell proliferation, differentiation of naive B cells into antibody-producing plasma cells and memory B cells, and immunoglobulin class switching.
Thus, these CD4+ T-helper cells may contribute to the formation of de novo DSA.
Schoenberger SP, Toes REM, van der Voort EIH, Offringa R. Melief CJM. T-Cell Help for Cytotoxic T Lymphocytes is Mediated by CD40–CD40L Interactions. Nature (1998) 393(6684):480–3. doi: 10.1038/31002
Lee RS, Grusby MJ, Glimcher LH, Winn HJ, Auchincloss H. Indirect Recognition by Helper Cells can Induce Donor-Specific Cytotoxic T Lymphocytes In Vivo. J Exp Med (1994) 179(3):865–72. doi: 10.1084/jem.179.3.865
Suciu-Foca N, Ciubotariu R, Itescu S, Rose E, Cortesini R. Indirect Allorecognition of Donor HLA-DR Peptides in Chronic Rejection of Heart Allografts. Transplant Proc (1998) 30(8):3999–4000. doi: 10.1016/S0041-1345(98)01318-9
21. Liu Z, Colovai AI, Tugulea S, Reed EF, Fisher PE, Mancini D, et al. Indirect Recognition of Donor HLA-DR Peptides in Organ Allograft Rejection. J Clin Invest (1996) 98(5):1150–7. doi: 10.1172/JCI118898
T helper cells play a role in cellular rejection and antibody mediated rejection, they provide help to CD8+ T cells so help graft directed CD8+ T cell response.(1)
CD4 T helper cells have an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching. (2)
Subtypes of T helper cells:
Th1 cells:
Secrete growth factor IL2 that increase proliferation of cytotoxic CD8+ T cells after allogenic stimulation. (3)
Induce delayed type hypersensitivity by macrophages and activate B cells to produce antibodies (3)
Th2 cells:
produce cytokines that facilitate humoral response particularly IgE production and activate eosinophils which may have a role in allograft rejection. (4)
Th17 cells:
secrete IL17 which has ability to recruit neutrophils, one of the first inflammatory effector cells to infiltrate allograft and cause damage. (5)
Th9 cells:
associated with variety of inflammatory diseases, involved in regulation of allergic inflammatory response which could be involved in allograft rejection.(6)
Th22 cells:
Have an important role in epidermal immunity, remodeling and auto immune disease. (7)
T follicular helper cells:
express CXCR5 which allow trafficking to B cell follicles, promote germinal center formation by providing help to B cells enabling their proliferation and differentiation into memory B cells & plasma cells that secrete high affinity antibodies. (8)
constitute a memory pool that recirculate in blood and is inactive in absence of antigen stimulation. (9)
Regulatory T cells:
important in mediating immune tolerance to self antigens
CD4+ CD25+Foxp3+ natural Tregs play a role in suppression of self reactive cells and are associated with better graft survival. (10)
The suppressive effects include secretion of anti-inflammatory cytokines, inhibition of T cell activation via tumor growth factor B, silence T cell genes responsible for production of cytokines via exosome carried microRNA, suppression of APC via CTLA-4 and induction of apoptosis via granzyme A/B, perforins & inducible cAMP. (11)
(1) Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol (2016) 7:582.
(2) Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH, et al. Two levels of help for B cell alloantibody production. J Exp Med (1996) 183:699–703
(3) Jiang S, Herrera O, Lechler RI. New spectrum ofallorecognition pathways: implications for graftrejection and transplantat ion tolerance. Curr OpinImmunol 2004;16:550–557
(4) Goldman M, Le Moine A, Braun M, Flamand V,Abramowicz D. A role for eosinophils intransplant rejection. Trends Immunol2001;22:247–251
(5) Agorogiannis, E.I., Regateiro, F.S., Howie, D., Waldmann, H. & Cobbold, S.P. (2012) Th17 cells induce a distinct graft rejection response that does not require IL-17A. American Journal of Transplantation, 12, 835.
(6)Askar, M., 2014. T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation. International journal of immunogenetics, 41(3), pp.185-194.
(7) Eyerich, S., Eyerich, K., Pennino, D., Carbone, T., Nasorri, F.,Pallotta, S. et al. (2009) Th22 cells represent a distinct humanT cell subset involved in epidermal immunity and remodeling.The Journal of Clinical Investigation, 119, 3573
(8) Crotty S: T follicular helper cell differentiation, function, and roles in
disease. Immunity 41: 529–542, 2014
(9) Asrir A, Aloulou M, Gador M, Pérals C, Fazilleau N: Interconnected subsets of memory follicular helper T cells have different effector functions. Nat Commun 8: 847, 2017
(10) L. Ma, H. Zhang, K. Hu, G. Lv, Y. Fu, D.A. Ayana, P. Zhao, Y. Jiang, The imbalance between Tregs, Th17 cells and inflammatory cytokines among renal transplant recipients, BMC Immunol. 16 (1) (2015) 56
(11) T. Vaikunthanathan, N. Safinia, D. Boardman, R.I. Lechler, G. Lombardi, Regulatory T cells: tolerance induction in solid organ transplantation, Clin. Exp. Immunol. 189 (2017) 197.
After activation of T cell by APC and initiation of the 3 signals, CD4+ T lymphocytes differentiate into several subclasses of T helpers and one regulatory subpopulation (T- reg), while CD8+ differentiate into cytotoxic T cell TCL.
Activated CD4+ T cells are subdivided into distinct functional categories depending on types cytokines secreted. The type of activated cells also depends on the site of antigen entry, the route of entry, the form of the antigen, and the amount of antigen.
Types of T helper cells:
Th1 — Th1 cells secrete IFN-gamma and IL-2. Th1 are involved in cellular cytotoxic response and activation of macrophages. T helper type 1 response is also responsible of antibodies production in particular IgG1.
Th2 — T helpers type 2 are involved in the development of allergic reaction through promotion of IgE and eosinophil activation. Th2 cells have major role in the development of asthma. Th2 cells produce IL-4, IL-5, IL-13, and IL-10. Th2 cells are active against parasitic infections.
Th17 — T helper type 17 cells secrete IL-17A, which induces production of pro inflammatory cytokines (IL-17F, IL-22, IL-26) and chemokines (CCL20) and recruits neutrophils .They have antibacterial and antifungal immune effect and involved in immune response in the settings of autoimmune diseases or chronic infections.
Th9– These cells have a role in autoimmune disease, anti-cancer and allergy. T helper type 9 cells produce IL-9 and IL-10. Th9 activation has a negative effect on the expression of CD40L in CD4 cells which cause reduced binding to the CD40 cells (B cells,DC and macrophages leading to decreased B cell expansion and IgG production.
Th22–Th22 cells are a major source of IL-22, although this cytokine is also produced by Th17. Th22 cells canhave a protective role in mucosal immunity cells, but deleterious effect in combination with IL17 causing autoimmune and inflammatory diseases, in particular psoriasis.
iTreg — Induced T regulatory (iTreg) cells can be induced in the periphery after antigen priming in the presence of retinoic acid and TGF-beta.
Tfh — T follicular helper (Tfh) cells are predominant in the secondary lymphoid organs. Tfh are activated by IL12.Upon activation, follicular T helpers have high affinity to bind B cells and subsequent differentiation and production of antibodies.
Tregs– are a specialized subpopulation of T cells that suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, NK cells, and Antigen Presenting Cells (APCs), thereby maintain the critical balance between selftolerance and autoimmunity. Tregs produce immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, that modulate APC functions, and can contribute to T effector cells suppression.
Th3 — T helper type 3 (Th3) cells are important in development and maintenance of induced Treg cells.
In clinical practice, the type of T helpers determines the activity of immune response as some of them induce B cells activation an maturation and subsequent antibody production and eventually AMR ( Th1, Th2, Th9, Th17, Th22, Thf) while others have role in immunosuppression and immunomodulation (Treg, iTreg, Th3).
Antibody molecules that are produced by plasma cells, represent an advanced stage in the B-cell development. After recognition of APC by TCR, and activation of T cells and further differentiation, and binding of Th CD4, the costimulatory pathway of CD40-CD40L is responsible for activation of B cells and differentiation into plasma cells, which are capable of antibody production and development of antibody mediated rejection.
References:
Handbook of kidney transplantation 6th edition
Uptodate
CD4 positive T cells is activated if APC express antigen in complexes with HLA class II
T helper cells which activate immune response and aid in rejection are :
1- T helper 1 which secrete IFN-gamma and IL-2 produce the following :
So it is the main mediator of cell mediated and antibody medicated rejection
2- T helper 2 which secrete IL-4, IL-5, and IL-13 that promote production of antibodies mainly IGE from plasma cells and are responsible for IgE-mediated atopic disease, immunity against parasitic infestations. (1)
3- T follicular helper provide help to B cells for production of antibodies, termed follicular because they are predominant in secondary lymphoid tissue
4- T helper 17 that secretes IL-17 which cause recruitment of neutrophils, responsible for immunity against extracellular bacteria and fungi and autoimmunity and play an impotent rule in graft rejection (2)
5- T helper 22 which secrete IL 22 which augment inflammatory effect of IL 17 secreted by T helper 17 when secreted with IL 17, has great importance in psoriasis, atopic dermatitis, bronchial asthma and has protective rule in mucosal immunity. (3)
6- T helper 9 secretes IL-9, IL 10, they have an important rule in allergy, autoimmune disease and immunity against tumors (4)
T helper cells which suppress immune response and aid in tolerance are :
1- Regulatory T cells which suppress the immune response and play main rule in maintenance of peripheral tolerance, although some express CD4 but others express CD25 or and Foxp3 (5)
2- Induced T regulatory (iTreg) cells which are regulatory T cells that are induced in the periphery after priming of antigen.
3- T helper type 3 (Th3) cells which are important for induction of mucosal tolerance and aid help for maintenance and development of induced T regulatory cells (6).
REFERANCES
1. Hancock WW, Sayegh MH, Kwok CA, et al. Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation. Transplantation 1993; 55:1112.
2. Chadha R, Heidt S, Jones ND, Wood KJ. Th17: contributors to allograft rejection and a barrier to the induction of transplantation tolerance? Transplantation 2011; 91:939.
3. Plank MW, Kaiko GE, Maltby S, et al. Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity. J Immunol 2017; 198:2182.
4- Schmitt E, Klein M, Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol 2014; 35:61.
5- Tsaur I, Gasser M, Aviles B, et al. Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. Kidney Int 2011; 79:1005.
6- Carrier Y, Yuan J, Kuchroo VK, Weiner HL. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol 2007; 178:179.
Good
The activated CD4+ T lymphocytes can differentiate into several distinct subtypes, which differ in their action and active immune mediators secreted (1). A collective summary of T cell differentiation is illustrated in the attached figure (1).
· T helper type 1 (Th1):
It acts via induction of cellular cytotoxicity and macrophage activation. Thus, it plays an essential role in eradicating intra-cellular organisms e.g viruses and mycobacteria and stimulating cytotoxic T cell maturation.
· T helper type 2 (Th2):
It is believed to play an important role in the immune response against parasitic infestations, particularly helminths, and they may have a role in the development of allergy and asthma
· T helper type 9 (Th9):
They are thought to have a role in the immune response against tumour cells, allergy, and autoimmune disease
· T helper type 17 (Th17):
It is thought to play a role in the immune response against extracellular pathogens like bacteria and fungi. Additionally, it may have a role in chronic inflammatory responses in chronic infection, allergy, and autoimmunity.
· T follicular helper (Tfh):
It is believed to have a role in activating B lymphocytes and augmentation of antibody production.
· T regulatory (Treg):
It is thought to be essential in developing and maintaining peripheral tolerance by negative feedback suppression of the immune response. It represents typically 1-2 % of the total CD4 population.
· Induced T regulatory (iTreg):
It can be induced in the periphery after antigen priming in the presence of TGF-beta.
· T helper type 3 (Th3):
It plays a role in mucosal tolerance induction and may promote the development and/or maintenance of induced Treg cells.
References:
1) Jennifer Heimall. The adaptive cellular immune response: T cells and cytokines. © 2021 UpToDate. (Accessed on 21 November 2021)
Excellent Ahmed
Well done
T helper cells differentiate into 4 major helper cells( Th1, Th2, Th17 & Thf) and one regulatory cell type( Treg).
Th1: is the prototype responsible for rejection.it produce IFNg, TNF alpha and lymphotoxin which promote allograft rejection by activating macrophages, directly damaging the endothelium, production of complement fixing IgG ab by B lymphocytes and stimulate the differentiation of CD8+ T lymphocytes to cytotoxic T lymphocytes.
Th2: responsible for allergic reaction but also have a role in rejection. They produce a variety of interleukins that activate eosinophils, basophils, and mast cells and enhance the production of ab.s that do not fix complement.
Th17: they produce IL 17 and promote allograft rejection by inducing inflammation
TFH: they provide help for B lymphocytes for ab production.
CD4+ T helper cells do not generally induce allograft rejection, their greater role in rejection is through providing help for cytotoxic CD8+ T cells.
Tregs which is CD54+ FOXP3+ T cells, provide potential control of alloimmunity and induction of tolerance through absorption of pro inflammatory IL2, CTLA4 mediated masking of CD80 & CD86 costimulatory ligand on antigen presenting cells, expression of immune inhibitory molecules & granzyme mediated killing of antigen presenting cells.
References:
Well done
Just missing Th9
Th9 is a functional subgroup of CD4+ T cells
It was first discovered at 2008.
Differentiated by cytokine transforming growth factor beta & IL4
PU.1 is a specific transcription factor for Th9 differentiation
Secret IL9 and recruit mast cells
Play important role in inflammatory diseases, autoimmune diseases, tumors.
Reference:
T helper cells express CD4, which is membrane glycoprotein, associated with T cell receptor (TCR), which facilitate binding of TCR to MHC II molecule.
Antigen binding to MHC II on dendritic cells leads to activation of naiive T helper cells to proliferate much more, then T helper cells will activate APCs like macrophages, dendritic cells and B cells as they express MHC II molecule and initiate its immune response.
CD4 cells or T helper cells have several subtypes, every type secrete different cytokines sharing in immune response.
CD4 cells activate cytotoxic cells , and APCs like macrophage and B cells and lead to its maturation and antibody formation.
CD4 protein bind also to HIV glycoprotein and all immunoglobulin classes.
CD4 cells which express CD25+ and has nucleated transcription factor FoxP3 are considered Treg cells which regulate and inhibit immune response and has a central role in immune tolerance
Madeleine V. Pahl, Nosratola D. Vaziri. Comprehensive clinical nephrology , Immune Function in Chronic Kidney Disease. 2010 4th ed
Emeka B. Okeke, Jude E. Uzonna. The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Front. Immunol.2019.
CD4 can recognize MHC II on donor APCs through TCR, and also recipient APCs can processed and present donor antigen to CD4 cells.
activation of CD4 will also activate CD8 which recognize MHC I of donor APCs.
also activated CD4 will stimulate and activate B cells to secrete antibodies ( B cells also is recipient APCs which processed and present donor antigen to CD4 cells).
T cells will not be fully activated except after 3 signals stimulation:
1- signal 1 through interaction or conjunction between TCR and MHC I (CD8), and MHC II ( CD4) on APCs.
2- signal 2 interaction between receptors CD28 (on T cells) and CD80/86/B7 on APCs upon another lock between CD154 (on T cells) and CD40 (on APCs )….co stimulatory pathway.
3- signal 3 interaction between CD25 on T cells and IL-2.
all these will stimulate T cells to produce cytokines and induce T cells proliferation, these cytokines will stimulate macrophages and B cells to produce antibodies (alloantibodies).
in very early period post-transplantation, the effect of ischemia will affect CD4 function and activation as ischemia will increase expression of HLA antigen and increase co stimulator proteins.
endothelial cells in the graft express MHC II which will be attacked by CD4 ends by antibodies formation and complement system activation with vascular injury and c4d deposition in antibody mediated rejection.
reference:
Rabab Al attas. transplant immunology lecture.
Thank Riham
Thanks Riham
What is the role of helper T cells in induction of tolerance?
Treg cells is one of helper cell subsets, and responsible for immune induction
Treg cells, subsets of T cells inhibit or regulate function of other immune cells so inhibit immune response to self and non-self antigens so prevent autoimmune diseases. It comes from differentiation of naiive Tcells outside thymus (periphery), and responsible for maintenance of peripheral tolerance, and has anti-tumor function.
Treg are CD4+CD25+, they express nuclear transcription factor FoxP3 which is responsible for its regulatory inhibitory function of Treg and can be used as a marker to monitor Treg post transplant.
Treg cells were activated by :
1- IL-2 lead to its clonal expansion and increased its number.
2- CD28 costimulation will lead to IL-2 secretion which increase Treg numbers.
Mechanism of Treg cells in inducing immune tolerance:
1- Release of inhibitory cytokines like IL-10, TGF-β and IL-35.
2- Treg cells mediate cell lysis by certain mediators like granzyme A and B , and perforin.
3- Apoptosis mediated by cytokine deprived state as Treg cells consume IL-2.
4- Modulate dendritic cell maturation or function; cytotoxic T lymphocyte antigen 4 (CTLA-4) interacts with CD-80/CD-86 and produce inhibitory pro apoptotic molecules.
Dario A. A. Vignali, Lauren W. Collison, Creg J. Workman. How regulatory T cells work. Nature Reviews Immunology 2008, volume 8, pages523–532.
SIMON READ, FIONA POWRIE, Regulatory T Cells. Handbook of clinical neurology. 2014.
Subsets of CD4+ cells
classical T-helper 1(Th1)
T-helper 2 (Th2) cells
T-helper 17(Th17)
follicular helper T cell (Tfh)
induced T-regulatory cells (iTreg)
regulatory type 1 cells (Tr1)
T-helper 9 (Th9)
Th1 Cells.
Th1 cells are involved with the elimination of intracellular pathogens and
Also are associated with organ specific autoimmunity
They secrete IFNγ, lymphotoxin α (Lfα), and IL2.
IFNγ is essential for the activation of mononuclear phagocytes. IFNγ is believed to exert its effect through
Lfα is associated with autoimmune diseases.
IL2 promotes proliferation of CD8+T cells with acquisition of cytolytic phenotype .
Besides its role as T cell growth factor, IL2 promotes the development of CD8+ memory cells after
antigen priming. Natural Treg (thymus derived) need IL2 for survival and activation.
Th2 Cells.
Th2 cells mount immune response to extracellular parasites, including helminthes.
The key effector-cytokines include IL4, IL5, IL9, IL13, IL10, IL25, and amphiregulin.
IL4 -involved in allergic inflammation
IL5- leads to activation and upregulation of eosinophils.
IL9-activates the function of mast cells, B cells,eosinophils, neutrophils as well as airway epithelial cells.
IL10- is an anti-inflammatory cytokine
IL13- combats gastrointestinal helminthes.
IL25- promotes Th2 responses, suppress Th17 response.
Th17 Cells
mount immune response against extracellular bacteria and fungi.
also involved in the generation of autoimmune diseases.
The key effector cytokines include IL17A, IL17F,IL21, and IL22.
Show plasticity .
Regulatory CD4+T Cells
Treg exists as natural thymus derived subset with expressed FOXP3
and as peripheral induced Treg cells, which arise from naıve CD4+CD25-cells.
Treg and Tr1 play important role in the maintenance of immunologic tolerance to self and foreign antigen.
effector cytokines include IL10, TGF β, and IL35.
Show plasticity and can reprogram into proinflammatory phenotypes in the presence of relevant cytokine milieu and cause more harm.
Follicular Helper (Tfh) T Cells.
play significant role in mediating humoral immunity through interaction with B-lymphocytes.
B cells undergo subsequent differentiation into Ig-producing plasma cells.
In the germinal area, they develop into B memory cells.
Tfh cells have been classified into Tfh1, Tfh2, and Tfh10.
Th9
Are a relatively new member in the Th cell family.
The signature cytokine for Th9 cells is IL-9, a cytokine in the IL-2Rγc-chain family.
Functionally, Th9 cells promote immune tolerance and protect against parasitic infections .
They also exert strong anti-tumor immunity.
Th9 cells also trigger prominent allergic inflammation, asthma, and autoimmune diseases, highlighting their pathological roles in the immune system.