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1、CD4+CD25+regulatory T cell Milestone for Treg cell discoveryA 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?1)THYMUS(nTreg,CD25+;SUPPRESS AUTOIMUNITY)2)PER
2、IPHERAL(iTreg,Tr1,Th3;DAMPEN IMMUNE REACTIONS TO PATHOGENS)Development of Treg in thymusDiversification of CD4 T Cell LineagesSearching for the markers of Treg cellsCD4+-Binds MHC class II-Expressed on Th cellsCD25+-Expressed on most Treg cellsCD3+-Ensures expression of TCRGITR-Negative signaling-Re
3、quired 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 conve
4、ntional 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(A
5、P-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
6、 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 specif
7、icity 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 sp
8、ecificities distinct from those of the original 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 cell
9、s 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
10、 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 APPLICATIONS
11、Effects 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 sub
12、clinical levels of pathogenic infection 2.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,lik
13、e 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
