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T Cell Subsets

T Cell Subsets . Yufang Shi University Professor Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School shiyu@umdnj.edu. Major Histocompatibility Complex Antigen and T Cells. Chromosome 17 H. Chromosome 17 H. -. -. 2 loci. 2 loci. CIITA.

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T Cell Subsets

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  1. T Cell Subsets Yufang Shi University Professor Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School shiyu@umdnj.edu

  2. Major Histocompatibility Complex Antigen and T Cells Chromosome 17 H Chromosome 17 H - - 2 loci 2 loci CIITA CIITA Complement Complement Cytokine Cytokine Gene encoding Gene encoding Ib Ib Involved antigen Involved antigen L L K K D D I I - - A I A I - - E E Processing Processing I I II II II II I I I I NKT cells 95% CD8 T cells CD4 5% CD8 T cells b Chromosome 2 2m Chromosome 1 Chromosome 1 CD1.1 CD1.1 CD1.2 CD1.2

  3. T cell subsets in MHC deficient mice Autoimmune _ _ _ + +/- _

  4. T Cell Activation Scharenberg et al. Nat Rev Immunol. 2007

  5. APC CD4 T CD4 Antigen recognition complex MHC II TCR CD28 CTLA4 CD40L ICOS Co-stimulatory pairs B7.1 B7.2 CD40 ICOSL Adhesion pairs ICAM-1 ICAM-2 LFA-3 LFA-1 CD2 Cytokine/Cytokine Receptors

  6. The Cytokine Network

  7. T Cell Subsets

  8. Reciprocal Cellular and Humoral Immune Responses Rats injected with repeated doses of flagellin (Salmonella adelaide) varying in doses developed specific antibody response (purple squares) and delayed-type hypersensitivity (DTH; red squares), Parish and Liew, 1972,

  9. The Discovery of Th1 and Th2 IL-4 IL-4 IL-4 J. Immunol. 1986

  10. Differential Expression of Cytokines by Th1 and Th2 cells

  11. In Vitro Generation of T Helper Subsets Naïve T Cells - CD3 - CD28 -IFN- IL-4 IL-6, TGFb Cytokine depletion -IFN- IL-4 TGFb -IFN- IL-4 -IL-4 IL-12 vv vv ThGM Th1 Th2 Th(i)17 Treg

  12. The role of transcription factors in the differentiation of TH1 and TH2 cells Biedermann et al., J Invest Derm Sym Proc 2004

  13. Th2 T Helper (CD4+ ) Subsets Antigen APC IL-4 Th0 IL-12 FasL Suicide Fas Th1 TRAIL DR4 Anti-Inflammatory Cytokines Pro-Inflammatory Cytokines IL-4 IL-10 IL-13 IL-5 IL-6 IFN-g IL-2 LT Th1 response Cellular Immunity DTH Th2 response Humoral Immunity Acute Hypersensitivity

  14. Th1/Th2 and Diseases • Autoimmune Diseases • Th1-organ specific: Arthritis, type I diabetes, Uveitis , • Inflammatory bowl disease (IBD) • Th2-systemic: Systemic Lupus Erythematosus • Chrones Disease • Infections • Th1-Intracellular: Leishmania major, Mycobacteria. • Th2-Extracellular: Worms, most bacteria

  15. Analysis of Th1 and Th2 Cells CON 5.1 4 - IL 10.2 - IFN g

  16. Cell Surface Markers on Th1, and Th2. 1. CD27 is negatively expressed on Th2 cells. 2. CD30 is preferentially expressed on Th2 cells. 3. IL-12Rb2 expressed on Th1 4. IFN-gRb expressed on Th2 5. CCR3 preferentially expressed on Th2.

  17. Th1 and Th2 Cells Do not Represent All CD4+ Cells CON 5.1 4 - IL 10.2 - IFN g

  18. Th17 and Treg Deenick and Tangye, Immunology and Cell Biology, 2009

  19. Th17 Differentiation

  20. Steps in the generation of Th17 cells. The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differentiation pathway. Th17 cells produce IL-21, which further amplifies Th17 generation in an autocrine manner. IL-21 also induces the IL-23R on differentiated Th17 cells to make them responsive to IL-23 signaling. IL-23 stabilizes the Th17 phenotype by secreting IL-17A, IL-17F and IL-22 and helping Th17 cells to acquire effector functions. STAT-3 plays an important role in Th17 differentiation, amplification and stabilization as IL-6, IL-21 and IL-23 signals through STAT-3. (Awasthi and Kuchroo, International Immunology, 2009)

  21. IL-17 • Produced by Th17, require the presence IL23 produced • by APC. • IL-17A–F (5 members) • IL-17A, prototype disulfide-linked homodimer • IL-17F, homodimer or hetrodimer with IL-17A. • Activation of IL-17R induces the production of cytokines such • as IL-1,IL-6 and TNF-a, and chermokines

  22. Th17 and Diseases •  Autoimmune disease: • Rheumatoid arthritis (CIA). • Multiple sclerosis (EAE) • Inflammatory bowel disease a • Psoriasis • High Th17 cells. IL-17 induce the production of IL-6, IL-8 and TNF- • Infections: • Important for both intracellularand extracellular pathogens. • IL-17 up-regulatesspecific chemokines, pro-inflammatory cytokines • and colony-stimulatingfactors (CSFs), thereby helping to induce • neutrophils and othermyeloid cells recruitment at the site of infection. • Bacterial: Mycobacteria andPneumocystis carinii • Fungal: candidiasis • Viral: HIV and others

  23. Regulatory CD4+ T Cells (Treg) CD25=IL-2Ra

  24. Regulatory CD4+ T Cells (Treg) • CD4+CD25+Foxp3+  Immunosuppressive • Anti-CD25 enhances immune response From Bubnoff

  25. Reciprocal generation of Treg and Th17 cells Activation of naive T cells in the presence of IL-23 did not induce the generation of Treg or Th17 cells. Supplementation of TGF-β in the culture induced the generation of Foxp3+ Treg cells while the addition of IL-6 not only inhibited the induction of TGF-β-induced Foxp3 but also concomitantly induced the generation of Th17 cells. (Awasthi and Kuchroo, International Immunology, 2009)

  26. Other T cell Subsets Th3: Produce TGF-b, but not IL-4 or IFN-g. CD8+ T cells: Cytotoxic Can also be differentiated into Tc1, Tc2…,. CD8+Foxp3+ cells have not been characterized CD8+ T cells are also immunosuppressive

  27. Complexity of Inflammatory Disorders

  28. Bettelli et al., Nature 2008

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