调节性T细胞课件.ppt

Milestone for Treg cell discoveryA special CD4+ T cellTreg is a special CD4+ T cellMost CD4+ T cells belong to Th1 or Th2But 5%-10% of CD4+T cells belong to neither one which is called CD4+ CD25+ regulator T cellsHeterogeneous groups of Treg cellsn nNatural Natural TregTreg cells cells ( (nTregnTreg) )n nInduced Induced TregTreg cells cellsn niTregiTregn nT Th h3 cells (TGF-3 cells (TGF- ) )n nTr1 (IL-10)Tr1 (IL-10)n nRegulatory CD8+T cellRegulatory CD8+T celln nRegulatory NK T cellRegulatory NK T celln nCD4-CD8- (DN) T cellsCD4-CD8- (DN) T cellsn n T cellsT cellsHow Tregs arise?1)THYMUS (nTreg, CD25+; SUPPRESS AUTOIMUNITY)2)PERIPHERAL (iTreg, Tr1, Th3; DAMPEN IMMUNE REACTIONS TO PATHOGENS)Development of Treg in thymusDiversification of CD4 T Cell LineagesSearching for the markers of Treg cellsMolecular MarkerMolecular MarkerFunctionFunctionCD4+-Binds MHC class II-Expressed on Th cellsCD25+-Expressed on most Treg cellsCD3+-Ensures expression of TCRGITR-Negative signaling-Required for survivalCTLA-4-Binds CD80/CD86-Antagonizes effects of CD28 to CD80/86CCR7-Mediates migration of Treg cells back to lymph nodesFoxp3-Required for differentiation and function of Treg cellsNOTE!There are no known cell surface molecules that uniquely distinguish the CD4+ Treg cells from conventional activated CD4+ T cells!CD25CTLA-4GITRCD4+CD25+RegulatoryT cell. FOXP3 is the specific marker - mediator of the geneticprogram governing CD25+CD4+ Treg celldevelopment and function. FOXP3 Controls Regulatory T Cell Function throughCooperation with NFATBy switching transcriptional partners Fos-Jun (AP-1)vs. FOXP3, NFAT converts the T cell activationprogram into the suppressor program of Tregs .Control of Treg function by FoxP3Treg activation and proliferationActivated by contact with DC (even immature!). Trafficking and localization of TregsBlood, lymphoid organs; variety of homing receptors necessary for migration to lymph nodes, sites of inflammation. Treg cell mediated phenomenon Bystander suppression Suppressive activity of Treg cells requires their prior activation through their T cell receptor; Once activated, Treg cells suppress in an antigen-nonspecific way; Treg cells with one antigen specificity can suppress effector T cells (Teff cells) with many other distinct antigen specificities.Treg cell mediated phenomenonInfectious tolerance/linked suppression Population of suppressor T cells creates a regulatory milieu and promotes the outgrowth of a new population of Treg cells with antigen specificities distinct from those of the original Treg population.Possible mechanisms of action of TregsIDO - indoleamine 2,3-dioxygenase Multiple Arena of TregTreg cell influence other T cellsSuppress the proliferation/cytokine release of both CD4 and CD8 Teff cells in vitroPrevent CD8+T cells from differentiation into effector T cells but not proliferation in vivoAlter the differentiation of nave CD4+T cell into IL-10/TGF-b secreting T cellsPrevent CD8+T cells from differentiation into effector T cellsbut not proliferation in vivoAlter the differentiation of nave CD4+T cell into IL-10/TGF-b secreting T cellsNaive CD4+T cell could differentiate into IL-10 or TGF- secreting induced Treg cells in the presence of Treg cells in in vivo and in vitroConsistent with the phenomenon of infectious tolerance/linked suppressionPRACTICAL CONSEQUENCES AND APPLICATIONSEffects of Treg deficiency in miceEffects of Treg deficiency in humansLimitation to targeting CD25 for Treg depletionnCD25, a component of the IL-2 receptor complex, is also upregulated on conventional activated (vaccine-induced) T cells.1.Interfere with an ongoing protective immune response against subclinical levels of pathogenic infection Treg rebound with timenA significant fraction of Treg (10-30%), especially recently activated Treg, have downregulated CD25.nDepletion is global - risk of autoimmune pathologyOther Treg-specific markersGITR, Lag-3, CTLA-4, CD103 - expressed on the cell surface but, like CD25, not specific.Foxp3Expression exclusively restricted to TregMaster regulator of suppressive phenotypeCD4+CD25+foxp3 as well as CD4+CD25-foxp3 Treg.Stimulate a CD8+ CTL response against foxp3Foxp3 is a nuclear protein - cannot use antibodies or ONTAK-like reagents for depletion of foxp3 expressing cells in vivoCo-vaccination against tumor antigen and foxp3LOSS OF Treg IN AUTOIMMUNE DISEASESGlobal Natural Treg Depletion in Active Systemic Lupus Erythematosus 。