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T helper subsetsPenny MorelMarch 23,20074-0343,morelpitt.eduOutlineTh cell subsetsRole of DCs in determining T cell effector functionFactors necessary for Th1/2 differentiationA new Th subset-ThIL-17Development and function of Treg in peripheryNave CD4+T cells can differentiate into several Teff and Treg typesImmunol.Rev.182:207,2001Th1/Th2/Th17 in diseaseAgent/DiseaseHostResponseOutcomeLeishmaniasisMTh1CureTh2ExacerbationLeprosyHTh1TuberculoidTh2LepromatousRA/MSHTh1Th1 cells in lesionHTh17Th17 in lesionsAllergyHTh2Th2 cytokines in lesionMTh17Induces PMNAc GVHDMTh1Th1 cytokines Chr GVHDMTh2Th2 cytokinesNature Rev.Immunol.3:984,2003Dendritic cells and T cell effector functionTh1/Th2 differentiationArise from a common precursorCytokinesAntigen doseCostimulatory moleculesDifferentiation results in expression of master regulators:GATA-3 for Th2 and T-bet for Th1Signaling molecules and transcription factors important in Th1/Th2 differentiationAnnu.Rev Immunol.21:713,2003Knockout mice that have defects in Th1 development:IFN-,IFN-R,IL-12,IL-12R,Stat4,IRF-1,ICSBP,T-betIL-12 is necessary for IFN-production,and IFN-is necessaryfor the induction of IL-12 responsiveness(acts via induction of T-bet)-stimulates expression of the IL-12R chain(signal transduction)IL-4 and IFN-are mutually antagonistic in Th1/Th2 development Source of IL-12:dendritic cells,macrophages.Certain pathogens stimulate secretion of large amounts of IL-12 by DC and macrophagesSource of IFN-:NK cells,Th1 cellsKnockout mice that have defects in Th2 development:IL-4,IL-13,IL-4R,Stat6GATA-3 antisense blocks Th2 developmentSource of IL-4Was thought to be either mast cells or CD4+NK1.1+T cells-but neither one was provenNow thought to come from developing Th2 cells-under the influence of IL-6,although IL-6 KO mice can still make some Th2 responses.It is possible that Th2 differentiation is the default pathway in the absence of IL-12Cytokines influence Th1/Th2 differentiationScience 260:547,1993Interleukin 420 kD protein produced by Th2 cells,mast cells,NKT cellsInduces proliferation of T cells and differentiation of Th2 cells;antagonizes Th1 differentiation Induces the expression of GATA-3 transcription factorIL-4 receptorAnnu.Rev.Immunol 17:701,1999Stat6Interleukin-12Heterodimeric cytokine IL-12p70-formed by two chains IL-12p40 and IL-12p35(encoded on different chromosomes)Produced by activated DC,macrophagesActs on NK and T cells to stimulate IFN-production;costimulates Th1 proliferation;enhances NK cytotoxic activity;induces Th1 differentiationIL12-R has two chains and 2;signals through stat 4IL-12 p40 can form homodimers and inhibit the action of IL-12p70IL-12 and IL-23ThIL-17 cellsProduce IL-17,IL-17F,IL-6,TNFIL-17 induces the production proinflammatory cytokines:TNF,IL-1,IL-6,IL-8ThIL-17 cells have been found in the diseased tissues of patients with RA,Lyme arthritis,MS,SLE and asthmaNew data suggest that this is a distinct lineage-development may require IL-6 and TGF-Cytokine requirements for ThIL-17Nature 44:235(2006)Annu.Rev.Immunol.1997.15:297-322.Antigen dose influences Th1/Th2 developmentVery high and very low dose leads to Th2 responseIntermediate dose leads to Th1 responseSame pattern is not always seen in complex antigensRole of DC subsets and antigen dose in the differentiation of Th1 or Th2 cellsJ.Exp Med.197:101.2003Other molecules implicated in Th1/Th2 differentiationCostimulatory molecules:CD86,B7-h bind to CD28 and ICOS resp.OX40(T cell)-OX40L(DC)-induced after activation,favor Th2Chemokines-differential expression of chemokine receptors of T cell subsets,different patterns of chemokine production by DC subsetsNew data suggest thatOX40L may play a rolein inducing inflammatorycytokines(TNF)J.Exp.Med.202:1213.2005Regulatory T cells in the peripheryNaturally occurring CD4+CD25+Tregs;develop in thymusTr1 cells-produce IL-10;induced following interaction with DC in presence of immunsuppressive cytokines Th3 cells-produce IL-10 and TGF-,usually found at mucosal surfacesJ.Immunol.171:6323,2003Mechanisms of SuppressionAlso induces FoxP3 expression in CD4+CD25-T cellsJI 176:6752,2006Seminars in Immunology 16:104,2004Nature Immunol.2:816,2001Nat.Rev.Immunol.6:613,2006GITR may play a role Picture likely to get even more complicated!
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