调节性T细胞课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Milestone for Treg cell discovery,Milestone for Treg cell discov,1,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 cells,A special CD4+ T cellTreg is a,2,Heterogeneous groups of Treg cells,Natural Treg cells (nTreg),Induced Treg cells,iTreg,Th3 cells (TGF-,),Tr1 (IL-10),Regulatory CD8+T cell,Regulatory NK T cell,CD4-CD8- (DN) T cells,T cells,Heterogeneous groups of Treg c,3,How Tregs arise?,THYMUS,(,nTreg, CD25,+,; SUPPRESS AUTOIM,UNIT,Y),PERIPHERAL,(,iTreg, Tr1, Th3; DAMPEN IMMUNE REACTIONS TO PATHOGENS),How Tregs arise?THYMUS (nTreg,4,Development of Treg in thymus,Development of Treg in thymus,5,Diversification of CD4 T Cell Lineages,Diversification of CD4 T Cell,6,Searching for the markers of Treg cells,Searching for the markers of T,7,调节性T细胞课件,8,NOTE!,There are no known cell surface molecules that uniquely distinguish the CD4,+,T,reg,cells from conventional activated CD4,+,T cells!,CD25,CTLA-4,GITR,CD4,+,CD25,+,Regulatory,T cell,NOTE!CD25CTLA-4GITRCD4+CD25+,9,.,FOXP3 is the specific marker -,mediator of the genetic,program governing CD25+CD4+ Treg cell,development and function,.,10,.,FOXP3 Controls Regulatory T Cell Function through,Cooperation with NFAT,By switching transcriptional partners Fos-Jun (AP-1),vs. FOXP3, NFAT converts the T cell activation,program into the suppressor program of Tregs,.,11,.,Control of Treg function by FoxP3,.Control of Treg function by F,12,Treg activation and proliferation,Activated by contact with DC (even immature!).,Treg activation and proliferat,13,调节性T细胞课件,14,调节性T细胞课件,15,调节性T细胞课件,16,Trafficking and,localization of Tregs,Blood, lymphoid organs; variety of homing receptors necessary for migration to lymph nodes, sites of inflammation.,Trafficking and,17,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 phenomenon,18,Treg cell mediated phenomenon,Infectious 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.,Treg cell mediated phenomenon,19,Possible mechanisms of action of Tregs,Possible mechanisms of action,20,调节性T细胞课件,21,IDO - indoleamine 2,3-dioxygenase,IDO - indoleamine 2,3-dioxygen,22,Multiple Arena of Treg,Multiple Arena of Treg,23,Treg cell influence other T cells,Suppress the proliferation/cytokine release of both CD4 and CD8 Teff cells,in vitro,Prevent CD8+T cells from differentiation into effector T cells but not proliferation,in vivo,Alter the differentiation of nave CD4+T cell into IL-10/TGF-b secreting T cells,Treg cell influence other T ce,24,Prevent CD8+T cells from differentiation into effector T cells,but not proliferation,in vivo,Prevent CD8+T cells from diffe,25,Alter the differentiation of nave CD4+T cell,into IL-10/TGF-b secreting T cells,Naive 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 vitro,Consistent with the phenomenon of infectious tolerance/linked suppression,Alter the differentiation of n,26,PRACTICAL CONSEQUENCES AND APPLICATIONS,PRACTICAL CONSEQUENCES AND APP,27,Effects of Treg deficiency in mice,Effects of Treg deficiency in,28,Effects of Treg deficiency in humans,Effects of Treg deficiency in,29,调节性T细胞课件,30,调节性T细胞课件,31,调节性T细胞课件,32,Limitation to targeting CD25 for Treg depletion,CD25, a component of the IL-2 receptor complex, is also upregulated on conventional activated (vaccine-induced) T cells.,Interfere with an ongoing protective immune response against subclinical levels of pathogenic infection,Treg rebound with time,A significant fraction of Treg (10-30%), especially recently activated Treg, have downregulated CD25.,Depletion is global - risk of autoimmune pathology,Limitation to targeting CD25 f,33,Other Treg-specific markers,GITR, Lag-3, CTLA-4, CD103 - expressed on the cell surface but, like CD25, not specific.,Foxp3,Expression exclusively restricted to Treg,Master regulator of suppressive phenotype,CD4+CD25+foxp3 as well as CD4+CD25-foxp3 Treg.,Other Treg-specific markersGIT,34,Stimulate a CD8+ CTL response against foxp3,Foxp3 is a nuclear protein - cannot use antibodies or ONTAK,-like reagents for depletion of foxp3 expressing cells,in vivo,Co-vaccination against tumor antigen and foxp3,Stimulate a CD8+ CTL response,35,LOSS OF Treg IN AUTOIMMUNE DISEASES,Global Natural Treg Depletion in Active Systemic Lupus Erythematosus,LOSS OF Treg IN AUTOIMMUNE DIS,36,37,调节性T细胞课件,38,