Th Th 表面標(biāo)志PPT課件

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頁/共39頁Nave CD4+ T cells can differentiate into several Teff and Treg types第2頁/共39頁Immunol. Rev. 182:207, 20

2、01第3頁/共39頁Th1/Th2/Th17 in diseaseAgent/DiseaseHostResponseOutcomeLeishmaniasisMTh1CureTh2ExacerbationLeprosyHTh1TuberculoidTh2LepromatousRA/MSHTh1Th1 cells in lesionHTh17Th17 in lesionsAllergyHTh2Th2 cytokines in lesionMTh17Induces PMNAc GVHDMTh1Th1 cytokines Chr GVHDMTh2Th2 cytokines第4頁/共39頁第5頁/共39

3、頁Nature Rev. Immunol. 3:984, 2003第6頁/共39頁Dendritic cells and T cell effector function第7頁/共39頁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第8頁/共39頁Signal

4、ing molecules and transcription factors important in Th1/Th2 differentiationAnnu. Rev Immunol. 21:713, 2003第9頁/共39頁Knockout 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 o

5、f 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

6、macrophagesSource of IFN-:NK cells, Th1 cells第10頁/共39頁Knockout 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 devel

7、oping 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第11頁/共39頁Cytokines influence Th1/Th2 differentiationScience 260:547, 1993第12頁/共39頁Interleukin 4 20 kD protein p

8、roduced 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第13頁/共39頁IL-4 receptorAnnu. Rev. Immunol 17:701, 1999Stat6第14頁/共39頁Interleukin-12 Heterodimeric cytokine

9、 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

10、; signals through stat 4 IL-12 p40 can form homodimers and inhibit the action of IL-12p70第15頁/共39頁第16頁/共39頁IL-12 and IL-23第17頁/共39頁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 disease

11、d 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- 第18頁/共39頁Cytokine requirements for ThIL-17Nature 44: 235 (2006) 第19頁/共39頁第20頁/共39頁Annu. Rev. Immunol. 1997. 15:297-322.Antigen dose influences Th

12、1/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頁/共39頁Role of DC subsets and antigen dose in the differentiation of Th1 or Th2 cellsJ. Exp Med. 197:101. 2003第22頁/共39頁Other molecules implica

13、ted 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第23頁/共3

14、9頁New data suggest thatOX40L may play a rolein inducing inflammatorycytokines (TNF)J. Exp. Med. 202:1213. 2005第24頁/共39頁第25頁/共39頁第26頁/共39頁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頁/共39頁第28頁/共39頁J. Immunol. 171:6323, 2003第29頁/共39頁第30頁/共39頁第31頁/共39頁第32頁/共39頁Mechanisms of Suppression第33頁/共39頁Also induces FoxP3 expression in CD4+ CD25- T cells