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1、CD4+CD25+regulatory T cell,Milestone for Treg cell discovery,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,Heterogeneous groups of Treg cells,Natural Treg cells (
2、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,How Tregs arise?,THYMUS (nTreg, CD25+; SUPPRESS AUTOIMUNITY) PERIPHERAL (iTreg, Tr1, Th3; DAMPEN IMMUNE REACTIONS TO PATHOGENS),Development of Treg in thymus,Diversif
3、ication of CD4 T Cell Lineages,Searching for the markers of Treg cells,NOTE! There are no known cell surface molecules that uniquely distinguish the CD4+ Treg cells from conventional activated CD4+ T cells!,.,FOXP3 is the specific marker - mediator of the genetic program governing CD25+CD4+ Treg cel
4、l development and function,.,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,.,Control of Treg function by FoxP3,Treg activation an
5、d proliferation Activated by contact with DC (even immature!).,Trafficking and localization of Tregs Blood, 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 cel
6、ls 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 Infect
7、ious 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 Tregs,IDO - indoleamine 2,3-dio
8、xygenase,Multiple Arena of Treg,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/T
9、GF-b secreting T cells,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,Naive CD4+T cell could differentiate into IL-10 or TGF- secreting induced Treg cells in the presence of
10、Treg cells in in vivo and in vitro Consistent with the phenomenon of infectious tolerance/linked suppression,PRACTICAL CONSEQUENCES AND APPLICATIONS,Effects of Treg deficiency in mice,Effects of Treg deficiency in humans,Limitation to targeting CD25 for Treg depletion,CD25, a component of the IL-2 r
11、eceptor 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 d
12、ownregulated CD25. Depletion is global - risk of autoimmune pathology,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.,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,LOSS OF Treg IN AUTOIMMUNE DISEASES Global Natural Treg Depletion in Active Systemic Lupus Erythematosus,