Th1╱Th2的流式检测

1、T helper subsetsPenny MorelMarch 23, 20074-0343, 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 peripheryNave CD4+ T cells can differentiate into severa

2、l 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 Ch

3、r GVHDMTh2Th2 cytokinesNature Rev. Immunol. 3:984, 2003Dendritic cells and T cell effector functionTh1/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 Th1Signalin

4、g 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 re

5、sponsiveness (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 macrophage

6、sSource 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 - u

7、nder 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 4 20 kD protein produced by Th2 cells, mast cells, NKT

8、 cells Induces 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-12 Heterodimeric cytokine IL-12p70 - formed by two chains IL-12p40 and IL-12p35

9、(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

10、and inhibit the action of IL-12p70IL-12 and IL-23ThIL-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 tissues of patients with RA, Lyme arthritis, MS, SLE and asthma New data suggest

11、 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

12、 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 differentiation Costimulatory molecules: CD86, B7-h bind to CD28 and ICOS resp. OX40 (T cell)-OX40L (DC) - induc

13、ed after activation, favor Th2 Chemokines - 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 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 surfacesJ. Immunol. 171:6323, 2003Mechanisms of SuppressionAlso