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  • 1. T helper subsets Penny Morel March 23, 2009 4-0343, morel@pitt.edu
  • 2. 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
  • 3. Naïve CD4+ T cells can differentiate into several Teff and Treg types
  • 4. Th1/Th2/Th17 in disease Agent/Disease Host Response Outcome Leishmaniasis M Th1 Cure Th2 Exacerbation Leprosy H Th1 Tuberculoid Th2 Lepromatous RA/MS H Th1 Th1 cells in lesion H Th17 Th17 in lesions Allergy H Th2 Th2 cytokines in lesion M Th17 Induces PMN Ac GVHD M Th1 Th1 cytokines Chr GVHD M Th2 Th2 cytokines
  • 5. Th subset differentiation • Arise from a common precursor • Cytokines • Antigen dose • Costimulatory molecules • Differentiation results in expression of master regulators - transcription factors
  • 6. Nature Rev. Immunol. 3:984, 2003
  • 7. Th1 differentiation: IL-12 is necessary for IFN- production, and IFN- is necessary for 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 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 macrophages Source of IFN- :
  • 8. Knockout mice that have defects in Th2 development: IL-4, IL-13, IL-4R, Stat6 GATA-3 antisense blocks Th2 development Source of IL-4 Was thought to be either mast cells or CD4+ NK1.1+ T cells - but neither one was proven Now 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 differentiation is the default pathway in
  • 9. Signaling molecules and transcription factors important in Th1/Th2 differentiation Annu. Rev Immunol. 21:713, 2003
  • 10. Cytokines influence Th1/Th2 differentiation Science 260:547, 1993
  • 11. Interleukin 4 • 20 kD protein produced 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
  • 12. IL-4 receptor Stat6 Annu. Rev. Immunol 17:701, 1999
  • 13. Interleukin-12 • Heterodimeric cytokine 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; signals through stat 4 • IL-12 p40 can form homodimers and inhibit the action of IL-12p70
  • 14. IL-12 and IL-23
  • 15. 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 tissues of patients with RA, Lyme arthritis, MS, SLE and asthma • Development requires IL-6, IL21, IL-23 and TGF- • ROR- t is the signature transcription factor
  • 16. Cytokine requirements for ThIL-17 Nature 44: 235 (2006)
  • 17. European Journal of Immunology, 2008 Volume 38 Pages 2636 - 2649
  • 18. European Journal of Immunology, 2008 Volume 38, Pages 2636 - 2649
  • 19. Induction of cytokine receptors in Th cell differentiation Zhu, J. et al. Blood 2008;112:1557-1569 Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
  • 20. Role of DC subsets and antigen dose in the differentiation of Th1 or Th2 cells J. Exp Med. 197:101. 2003
  • 21. Th2 differentiation at low antigen dose Zhu, J. et al. Blood 2008;112:1557-1569 Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
  • 22. 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 receptors of T cell subsets, different patterns of chemokine production by DC subsets
  • 23. Crossregulation during Th cell differentiation Zhu, J. et al. Blood 2008;112:1557-1569 Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
  • 24. 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 • Induced Treg - induced in presence of TGF- express Foxp3
  • 25. Mechanisms of Suppression
  • 26. Seminars in Immunology 16:104, 2004
  • 27. Nature Immunol. 2:816, 2001