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  • 1. Regulation of the Immune Response April 23, 2008 Penny Morel 4-0343, morel@pitt.edu
  • 2. Levels of Immune regulation
    • Homeostatic control
    • Peripheral tolerance to self antigens
    • Initiation and termination of immune responses to foreign antigens
    • Immunological memory
  • 3. Homeostatic Control
    • Number of immune cells is tightly controlled
    • T cells “sense” if number are low - transfer of T cells to T cell-deficient mouse results in rapid proliferation of the transferred cells
    • Survival of naïve, activated and memory cells has different requirements
  • 4. Nature Immunol. 1:107, 2000
  • 5. Nature Reviews Immunology 2, 547-556 (2002)
  • 6. Peripheral T cell tolerance
    • Immune privilege
    • Anergy
    • Deletion: Activation induced cell death
    • Suppression
  • 7. Figure 13-12
  • 8. Mechanisms of immune privilege
    • Atypical communication between tissue and immune system: no lymphatic drainage or tissue barrier
    • Secretion of immunosuppressive cytokines such as TGF- 
    • Expression of FasL on tissue cells: induce apoptosis of Fas-expressing immune cells
  • 9. Nature Rev. Immunol. 2:11, 2002 Peripheral Self Tolerance
  • 10. Nature Rev. Immunol. 2:11, 2002
  • 11. Nature Rev. Immunol. 2:11, 2002
  • 12. DC in steady state induce tolerance Proc Natl Acad Sci U S A 2002 99:351-8
  • 13. How is peripheral tolerance broken? Nature Rev. Immunol. 2:11, 2002
  • 14. Initiation and termination of immune response
    • Antigen type, dose, route
    • APC in response initiation
    • Antigen removal: cells die by neglect
    • CTLA-4: inhibits T cell activation
    • AICD: actively deletes cells through action of Fas/FasL
  • 15. Science 280:243. 1998
  • 16. Immunity 16:23, 2002
  • 17.  
  • 18. Science 280:243. 1998
  • 19.  
  • 20. Regulatory/suppressor T cells
    • CD4 + CD25 + CD45RB lo CD62L + suppressor T cells
    • Regulatory T cells in mucosal surfaces
    • Tr1 cells
    • CD8 + CD28 - suppressor cells in human
  • 21.  
  • 22. No specific cell surface markers
    • CTLA-4 expressed constitutively, ? Role in T reg development
    • CD25 - IL-2 important for T reg survival. Can rescue IL-2R  -/- mice with wild type T reg cells - puts into question role of IL-2 in AICD
    • CD28 necessary for T reg development
    • GITR (TNFRSF18) appears to attenuate suppression - X-link GITR reduces suppression
  • 23. IL-2 is required for development and maintenance of Tregs J Exp Med. 2005 201:723-35
  • 24. J Exp Med. 2005 201:723-35
  • 25. Immunity 12:431, 2000
  • 26. Immunity 12:431, 2000
  • 27. Immunity 12:431, 2000 T cell transfer into A. NOD-Scid or B. CD28 -/- mice
  • 28. GITR
  • 29.  
  • 30. GITRL is expressed on APC and is downregulated following activation J. Immunol. 173:5008, 2004
  • 31. GITR expression on CD25 - T cells abrogates suppression GITR -/- None 25 + GITR -/- 25 - Filled symbols Anti-GITR Ab 25 + and 25 - J. Immunol. 173:5008, 2004
  • 32. Nat. Rev. Immunol. 6:613, 2006 GITR may play a role in costimulation
  • 33. CD103 (an integrin) is necessary for suppression of colitis
  • 34. CD103 expression on DCs is required for suppression of colitis
  • 35.  
  • 36. Lethal autoimmune disease in CTLA-4 -/- mice requires B7 molecules. Lack of stimulation can be reversed by adding anti-CD28 mAb. J. Exp. Med. 189:435, 1999
  • 37. CTLA-4 -/- mice make normal #s of T regs Eur J Immunol. 2004 34:2996-3005 .
  • 38. In wild type mice CTLA-4 is important for in vitro suppression CTLA-4 -/- T regs can still suppress Eur J Immunol. 2004 34:2996-3005 .
  • 39. CD4 cells from WT CD4 cells from TKO
  • 40.  
  • 41.  
  • 42. Production of active TGF-  a very complex cytokine Annu. Rev. Immunol. 16:137, 1998
  • 43.  
  • 44. TGF-  induces T regs Can suppress Express FoxP3 J. Exp Med. 198:1875. 2003
  • 45.  
  • 46. Nature. 2002 420:502-7. T regs in Leishmania- infected mice Present in lesions Secrete IL-10 Suppressor function
  • 47. T regs in infectious disease Nature. 2002 420:502-7.
  • 48.