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 cellsHow Tregs arise?1)THYMUS (nTreg, CD25+; SUPPRESS AUTOIMUNITY)2)PERIPHERAL (iTreg, Tr1, Th3; DAMPEN IMMUNE REACTIONS T
2、O 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 of CD28 to CD80/86CCR7-M
3、ediates 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
4、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
5、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 mediate
6、d 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 d
7、istinct 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.
8、Possible mPossible mechanisms of action of echanisms 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 differentiation into effect
9、or 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
10、 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
11、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
12、 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
13、 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
