Type 1 and Type 2 helper cells - University of Medicine and ...
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Type 1 and Type 2 helper cells - University of Medicine and ... Type 1 and Type 2 helper cells - University of Medicine and ... Presentation Transcript

  • T Cell Subsets Yufang Shi University Professor Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School [email_address]
  • Major Histocompatibility Complex Antigen and T Cells I I I II II K D L Gene encoding Involved antigen Processing I - A I - E Complement Cytokine Chromosome 17 H - 2 loci 95% CD8 T cells CD4 5% CD8 T cells CD1.1 Chromosome 1 CD1.2 NKT cells Ib CIITA I I I II II K D L Gene encoding Involved antigen Processing I - A I - E Complement Cytokine Chromosome 17 H - 2 loci CD1.1 Chromosome 1 CD1.2 Ib CIITA Chromosome 2  2m
  • T cell subsets in MHC deficient mice Autoimmune _ _ _ + +/- _
  • Scharenberg et al. Nat Rev Immunol. 2007 T Cell Activation
  • APC CD4 T MHC II TCR CD4 Antigen recognition complex B7.1 B7.2 CD40 ICOSL CD28 CTLA4 CD40L ICOS Co-stimulatory pairs ICAM-1 ICAM-2 LFA-3 LFA-1 CD2 Adhesion pairs Cytokine/Cytokine Receptors
  • The Cytokine Network
  • T Cell Subsets
  • 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, Reciprocal Cellular and Humoral Immune Responses
  • The Discovery of Th1 and Th2 J. Immunol. 1986 IL-4 IL-4 IL-4
  • Differential Expression of Cytokines by Th1 and Th2 cells Cytokine Th1 Th2 Th0 Thp IFN-  + - + - LT (TNF  + - - IL-2 + - + + IL-3 + + + - GM-CSF + + + - TNF-  + + MIP-  + + MIP-1  + + TCA-3 + + IL-4 - + + - IL-5 - + + - IL-6 - + IL-9 - + IL-10 - + - IL-13 - +
  • In Vitro Generation of T Helper Subsets Naïve T Cells Th1 Th2  -IFN-  IL-4  -IL-4 IL-12  - CD3  - CD28 Treg Cytokine depletion Th(i)17  -IFN-  IL-4 IL-6, TGF  vv  -IFN-  IL-4 TGF  vv ThGM
  • Biedermann et al., J Invest Derm Sym Proc 2004 The role of transcription factors in the differentiation of TH1 and TH2 cells
  • T Helper (CD4 + ) Subsets Th2 response Humoral Immunity Acute Hypersensitivity IL-4 IL-10 IL-13 IL-5 IL-6 Anti-Inflammatory Cytokines TRAIL IL-4 Th0 IFN-  IL-2 LT Pro-Inflammatory Cytokines Th1 FasL DR4 Th1 response Cellular Immunity DTH Suicide Fas Antigen APC IL-12 Th2
  • 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
  • Analysis of Th1 and Th2 Cells 10.2 5.1 CON IL - 4 IFN - 
  • 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.
  • Th1 and Th2 Cells Do not Represent All CD4 + Cells 10.2 5.1 CON IL - 4 IFN - 
  • Th1 7 and Treg Deenick and Tangye, Immunology and Cell Biology, 2009
  • Th1 7 Differentiation
  • 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)
    • 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-  and chermokines
    IL-17
  • Th1 7 and Diseases
    •   Autoimmune disease:
    • Rheumatoid arthritis (CIA).
    • Multiple sclerosis (EAE)
    • Inflammatory bowel disease a
    • Psoriasis
    • High T h 17 cells. IL-17 induce the production of IL-6, IL-8 and TNF-
    • Infections:
    • Important for both intracellular and extracellular pathogens.
    • IL-17 up-regulates specific chemokines, pro-inflammatory cytokines
    • and colony-stimulating factors (CSFs), thereby helping to induce
    • neutrophils and other myeloid cells recruitment at the site of infection.
    • Bacterial: Mycobacteria and Pneumocystis carinii
    • Fungal: candidiasis
    • Viral: HIV and others
  • Regulatory CD4 + T Cells (Treg) CD25=IL-2R 
  • Regulatory CD4 + T Cells (Treg)
    • CD4 + CD25 + Foxp3 +  Immunosuppressive
    • Anti-CD25 enhances immune response
    From Bubnoff
  • (Awasthi and Kuchroo, International Immunology, 2009) 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.
  • 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 Other T cell Subsets
  • Complexity of Inflammatory Disorders
  • Bettelli et al., Nature 2008