ThTh表面标志学习课程

1、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第1页/共39页第一页，编辑于星期日：点 十七分。Nave CD4+ T cells can differentiate into several Teff and Treg types第2页/共39页第二页，编辑于星

2、期日：点 十七分。Immunol. Rev. 182:207, 2001第3页/共39页第三页，编辑于星期日：点 十七分。Th1/Th2/Th17 in diseaseAgent/DiseaseHostResponse OutcomeLeishmaniasisMTh1CureTh2ExacerbationLeprosyHTh1TuberculoidTh2LepromatousRA/MSHTh1Th1 cells in lesionHTh17Th17 in lesionsAllergyHTh2Th2 cytokines in lesionMTh17Induces PMNAc GVHDMTh1Th

3、1 cytokines Chr GVHDMTh2Th2 cytokines第4页/共39页第四页，编辑于星期日：点 十七分。第5页/共39页第五页，编辑于星期日：点 十七分。Nature Rev. Immunol. 3:984, 2003第6页/共39页第六页，编辑于星期日：点 十七分。Dendritic cells and T cell effector function第7页/共39页第七页，编辑于星期日：点 十七分。Th1/Th2 differentiation Arise from a common precursor Cytokines Antigen dose Costimulat

4、ory molecules Differentiation results in expression of master regulators: GATA-3 for Th2 and T-bet for Th1第8页/共39页第八页，编辑于星期日：点 十七分。Signaling molecules and transcription factors important in Th1/Th2 differentiationAnnu. Rev Immunol. 21:713, 2003第9页/共39页第九页，编辑于星期日：点 十七分。Knockout mice that have defects

5、 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 ant

6、agonistic 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 cells第10页/共39页第十页，编辑于星期日：点 十七分。Knockout mice that have defects in Th2 development:IL-4, IL-13, IL-4R, Stat

7、6GATA-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 di

8、fferentiation is the default pathway in the absence of IL-12第11页/共39页第十一页，编辑于星期日：点 十七分。Cytokines influence Th1/Th2 differentiationScience 260:547, 1993第12页/共39页第十二页，编辑于星期日：点 十七分。Interleukin 4 20 kD protein produced by Th2 cells, mast cells, NKT cells Induces proliferation of T cells and differentiat

9、ion of Th2 cells; antagonizes Th1 differentiation Induces the expression of GATA-3 transcription factor第13页/共39页第十三页，编辑于星期日：点 十七分。IL-4 receptorAnnu. Rev. Immunol 17:701, 1999Stat6第14页/共39页第十四页，编辑于星期日：点 十七分。Interleukin-12 Heterodimeric cytokine IL-12p70 - formed by two chains IL-12p40 and IL-12p35 (e

10、ncoded 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 an

11、d inhibit the action of IL-12p70第15页/共39页第十五页，编辑于星期日：点 十七分。第16页/共39页第十六页，编辑于星期日：点 十七分。IL-12 and IL-23第17页/共39页第十七页，编辑于星期日：点 十七分。ThIL-17 cells Produce IL-17, IL-17F, IL-6, TNF IL-17 induces the production proinflammatory cytokines: TNF, IL-1, IL-6, IL-8 ThIL-17 cells have been found in the diseased t

12、issues 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- 第18页/共39页第十八页，编辑于星期日：点 十七分。Cytokine requirements for ThIL-17Nature 44: 235 (2006) 第19页/共39页第十九页，编辑于星期日：点 十七分。第20页/共39页第二十页，编辑于星期日：点 十七分。Annu. Rev. I

13、mmunol. 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 antigens第21页/共39页第二十一页，编辑于星期日：点 十七分。Role of DC subsets and antigen dose in the differentiation of Th1

14、 or Th2 cellsJ. Exp Med. 197:101. 2003第22页/共39页第二十二页，编辑于星期日：点 十七分。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 rec

15、eptors of T cell subsets, different patterns of chemokine production by DC subsets第23页/共39页第二十三页，编辑于星期日：点 十七分。New data suggest thatOX40L may play a rolein inducing inflammatorycytokines (TNF)J. Exp. Med. 202:1213. 2005第24页/共39页第二十四页，编辑于星期日：点 十七分。第25页/共39页第二十五页，编辑于星期日：点 十七分。第26页/共39页第二十六页，编辑于星期日：点 十七

16、分。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-, usually found at mucosal surfaces第27页/共39页第二十七页，编辑于星期日：点 十七分。第2

17、8页/共39页第二十八页，编辑于星期日：点 十七分。J. Immunol. 171:6323, 2003第29页/共39页第二十九页，编辑于星期日：点 十七分。第30页/共39页第三十页，编辑于星期日：点 十七分。第31页/共39页第三十一页，编辑于星期日：点 十七分。第32页/共39页第三十二页，编辑于星期日：点 十七分。Mechanisms of Suppression第33页/共39页第三十三页，编辑于星期日：点 十七分。Also induces FoxP3 expression in CD4+ CD25- T cellsJI 176:6752, 2006第34页/共39页第三十四页，编辑于星期日：点 十七分。Seminars in Immunology 16:104, 200