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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,T helper subsets,Penny Morel,March 23,2007,4-0343,morelpitt.edu,Outline,Th,cell subsets,Role of,DCs,in determining T cell,effector,function,Factors necessary for Th1/2 differentiation,A new,Th,subset-ThIL-17,Development and function of,Treg,in periphery,Nave CD4,+,T cells can differentiate into several,T,eff,and,T,reg,types,Immunol,.Rev.182:207,2001,Th1/Th2/Th17 in disease,Agent/DiseaseHostResponseOutcome,Leishmaniasis,MTh1Cure,Th2Exacerbation,LeprosyHTh1,Tuberculoid,Th2,Lepromatous,RA/MSHTh1Th1 cells in lesion,HTh17Th17 in lesions,AllergyHTh2Th2 cytokines in,lesion,MTh17Induces PMN,Ac GVHDMTh1Th1 cytokines,Chr,GVHDMTh2Th2 cytokines,Nature Rev.,Immunol,.3:984,2003,Dendritic,cells and T cell,effector,function,Th1/Th2 differentiation,Arise from a common precursor,Cytokines,Antigen dose,Costimulatory,molecules,Differentiation results in expression of master regulators:GATA-3 for Th2 and T-bet for Th1,Signaling molecules and transcription factors important in Th1/Th2 differentiation,Annu,.Rev,Immunol,.21:713,2003,Knockout mice that have defects in Th1 development,:,IFN-,IFN-,R,IL-12,IL-12R,Stat4,IRF-1,ICSBP,T-bet,IL-12 is necessary for IFN-,production,and IFN-,is necessary,for 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 macrophages,Source of IFN-,:,NK cells,Th1 cells,Knockout mice that have defects in Th2 development,:,IL-4,IL-13,IL-4R,Stat6,GATA-3,antisense,blocks Th2 development,Source of IL-4,Was thought to be either mast cells or CD4,+,NK1.1,+,T cells-,but neither one was proven,Now 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-12,Cytokines influence Th1/Th2 differentiation,Science 260:547,1993,Interleukin 4,20,kD,protein produced by Th2 cells,mast cells,NKT cells,Induces proliferation of T cells and differentiation of Th2 cells;antagonizes Th1 differentiation,Induces the expression of GATA-3 transcription factor,IL-4 receptor,Annu.Rev.,Immunol,17:701,1999,Stat6,Interleukin-12,Heterodimeric,cytokine IL-12p70-formed by two chains IL-12p40 and IL-12p35(,encoded on different chromosomes),Produced by activated DC,macrophages,Acts on NK and T cells to stimulate IFN-,production;,costimulates,Th1 proliferation;enhances NK cytotoxic activity;induces Th1 differentiation,IL12-R has two chains,and,2;signals through stat 4,IL-12 p40 can form,homodimers,and inhibit the action of IL-12p70,IL-12 and IL-23,Th,IL-17,cells,Produce IL-17,IL-17F,IL-6,TNF,IL-17 induces the production,proinflammatory,cytokines:TNF,IL-1,IL-6,IL-8,Th,IL-17,cells have been found in the diseased tissues of patients with RA,Lyme arthritis,MS,SLE and asthma,New data suggest that this is a distinct lineage-development may require IL-6 and TGF-,Cytokine requirements for Th,IL-17,Nature 44:235(2006),Annu.Rev.,Immunol,.1997.15:297-322.,Antigen dose influences Th1/Th2 development,Very high and very low dose leads to Th2 response,Intermediate dose leads to Th1 response,Same pattern is not always seen in complex antigens,Role of DC subsets and antigen dose in the differentiation of Th1 or Th2 cells,J.Exp Med.197:101.2003,Other molecules implicated in Th1/Th2 differentiation,Costimulatory,molecules:CD86,B7-h bind to CD28 and ICOS,resp,.,OX40(T cell)-OX40L(DC)-induced after activation,favor Th2,Chemokines,-differential expression of,chemokine,receptors of T cell subsets,different patterns of,chemokine,production by DC subsets,New data suggest that,OX40L may play a role,in inducing inflammatory,cytokines(TNF),J.Exp.Med.202:1213.,2005,Regulatory T cells in the periphery,Naturally occurring CD4,+,CD25,+,Tregs,;develop in thymus,Tr1 cells-produce IL-10;induced following interaction with DC in presence of,immunsuppressive,cytokines,Th3 cells-produce IL-10 and TGF-,b,usually found at mucosal surfaces,J.,Immunol,.171:6323,2003,Mechanisms of Suppression,Also induces FoxP3 expression in,CD4,+,CD25,-,T cells,JI 176:6752,2006,Seminars in Immunology 16:104,2004,Nature,Immunol,.2:816,2001,Nat.Rev.,Immunol,.6:613,2006,GITR may play a role,Picture likely to get even more complicated!,
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