調(diào)節(jié)性T細胞ppt課件

1、CD4+CD25+regulatory T cell A special CD4+ T cell Treg is a special CD4+ T cell Most CD4+ T cells belong to Th1 or Th2 But 5%-10% of CD4+T cells belong to neither one which is called CD4+ CD25+ regulator T cellsHow Tregs arise?THYMUS (nTreg, CD25+; SUPPRESS AUTOIMUNITY)PERIPHERAL (iTreg, Tr1, Th3; DA

2、MPEN IMMUNE REACTIONS TO PATHOGENS)Development of Treg in thymusDiversification of CD4 T Cell LineagesCD4+-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 o

3、f 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+Regulato

4、ryT 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 activationprogr

5、am 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 inflamma

6、tion. 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 c

7、ells) 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 or

8、iginal Treg population.Possible mechanisms of action of Possible mechanisms of action of TregsTregsIDO - 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 diff

9、erentiation 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 secre

10、ting 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 miceEffe

11、cts 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.nInterfere with an ongoing protective immune response against subclinical levels of pathogenic infec

12、tion nTreg 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 rea