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Regulation of the Immune Response April 23, 2008 Penny Morel 4-0343, morel@pitt.edu
Levels of Immune regulation <ul><li>Homeostatic control </li></ul><ul><li>Peripheral tolerance to self antigens </li></ul>...
Homeostatic Control <ul><li>Number of immune cells is tightly controlled </li></ul><ul><li>T cells “sense” if number are l...
Nature Immunol. 1:107, 2000
Nature Reviews Immunology 2, 547-556 (2002)
Peripheral T cell tolerance <ul><li>Immune privilege </li></ul><ul><li>Anergy </li></ul><ul><li>Deletion: Activation induc...
Figure 13-12
Mechanisms of immune privilege <ul><li>Atypical communication between tissue and immune system: no lymphatic drainage or t...
Nature Rev. Immunol. 2:11, 2002 Peripheral Self Tolerance
Nature Rev. Immunol. 2:11, 2002
Nature Rev. Immunol. 2:11, 2002
DC in steady state induce tolerance Proc Natl Acad Sci U S A 2002 99:351-8
How is peripheral tolerance broken? Nature Rev. Immunol. 2:11, 2002
Initiation and termination of immune response <ul><li>Antigen type, dose, route </li></ul><ul><li>APC in response initiati...
Science 280:243. 1998
Immunity 16:23, 2002
 
Science 280:243. 1998
 
Regulatory/suppressor T cells <ul><li>CD4 +  CD25 +  CD45RB lo  CD62L +  suppressor T cells </li></ul><ul><li>Regulatory T...
 
No specific cell surface markers <ul><li>CTLA-4 expressed constitutively, ? Role in T reg development </li></ul><ul><li>CD...
IL-2 is required for development and maintenance of Tregs J Exp Med. 2005 201:723-35
J Exp Med. 2005 201:723-35
Immunity 12:431, 2000
Immunity 12:431, 2000
Immunity 12:431, 2000 T cell transfer into A. NOD-Scid or B. CD28 -/- mice
GITR
 
GITRL is expressed on APC and is downregulated following activation J. Immunol. 173:5008, 2004
GITR expression on CD25 -  T cells abrogates suppression GITR -/- None 25 + GITR -/- 25 - Filled symbols Anti-GITR Ab 25 +...
Nat. Rev. Immunol. 6:613, 2006 GITR may play a role in costimulation
CD103 (an integrin) is necessary for suppression of colitis
CD103 expression on DCs is required for suppression of colitis
 
Lethal autoimmune disease in CTLA-4 -/- mice requires B7 molecules. Lack of stimulation can be reversed by adding anti-CD2...
CTLA-4 -/- mice make normal #s of T regs Eur J Immunol. 2004 34:2996-3005 .
In wild type mice CTLA-4 is important for  in vitro  suppression  CTLA-4 -/- T regs can still suppress Eur J Immunol. 2004...
CD4 cells from WT CD4 cells from TKO
 
 
Production of active TGF-  a very complex cytokine Annu. Rev. Immunol. 16:137, 1998
 
TGF-   induces T regs Can suppress Express FoxP3 J. Exp Med. 198:1875. 2003
 
Nature. 2002 420:502-7. T regs in Leishmania- infected mice Present in lesions Secrete IL-10 Suppressor function
T regs in infectious disease Nature. 2002 420:502-7.
 
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  1. 1. Regulation of the Immune Response April 23, 2008 Penny Morel 4-0343, morel@pitt.edu
  2. 2. Levels of Immune regulation <ul><li>Homeostatic control </li></ul><ul><li>Peripheral tolerance to self antigens </li></ul><ul><li>Initiation and termination of immune responses to foreign antigens </li></ul><ul><li>Immunological memory </li></ul>
  3. 3. Homeostatic Control <ul><li>Number of immune cells is tightly controlled </li></ul><ul><li>T cells “sense” if number are low - transfer of T cells to T cell-deficient mouse results in rapid proliferation of the transferred cells </li></ul><ul><li>Survival of naïve, activated and memory cells has different requirements </li></ul>
  4. 4. Nature Immunol. 1:107, 2000
  5. 5. Nature Reviews Immunology 2, 547-556 (2002)
  6. 6. Peripheral T cell tolerance <ul><li>Immune privilege </li></ul><ul><li>Anergy </li></ul><ul><li>Deletion: Activation induced cell death </li></ul><ul><li>Suppression </li></ul>
  7. 7. Figure 13-12
  8. 8. Mechanisms of immune privilege <ul><li>Atypical communication between tissue and immune system: no lymphatic drainage or tissue barrier </li></ul><ul><li>Secretion of immunosuppressive cytokines such as TGF-  </li></ul><ul><li>Expression of FasL on tissue cells: induce apoptosis of Fas-expressing immune cells </li></ul>
  9. 9. Nature Rev. Immunol. 2:11, 2002 Peripheral Self Tolerance
  10. 10. Nature Rev. Immunol. 2:11, 2002
  11. 11. Nature Rev. Immunol. 2:11, 2002
  12. 12. DC in steady state induce tolerance Proc Natl Acad Sci U S A 2002 99:351-8
  13. 13. How is peripheral tolerance broken? Nature Rev. Immunol. 2:11, 2002
  14. 14. Initiation and termination of immune response <ul><li>Antigen type, dose, route </li></ul><ul><li>APC in response initiation </li></ul><ul><li>Antigen removal: cells die by neglect </li></ul><ul><li>CTLA-4: inhibits T cell activation </li></ul><ul><li>AICD: actively deletes cells through action of Fas/FasL </li></ul>
  15. 15. Science 280:243. 1998
  16. 16. Immunity 16:23, 2002
  17. 18. Science 280:243. 1998
  18. 20. Regulatory/suppressor T cells <ul><li>CD4 + CD25 + CD45RB lo CD62L + suppressor T cells </li></ul><ul><li>Regulatory T cells in mucosal surfaces </li></ul><ul><li>Tr1 cells </li></ul><ul><li>CD8 + CD28 - suppressor cells in human </li></ul>
  19. 22. No specific cell surface markers <ul><li>CTLA-4 expressed constitutively, ? Role in T reg development </li></ul><ul><li>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 </li></ul><ul><li>CD28 necessary for T reg development </li></ul><ul><li>GITR (TNFRSF18) appears to attenuate suppression - X-link GITR reduces suppression </li></ul>
  20. 23. IL-2 is required for development and maintenance of Tregs J Exp Med. 2005 201:723-35
  21. 24. J Exp Med. 2005 201:723-35
  22. 25. Immunity 12:431, 2000
  23. 26. Immunity 12:431, 2000
  24. 27. Immunity 12:431, 2000 T cell transfer into A. NOD-Scid or B. CD28 -/- mice
  25. 28. GITR
  26. 30. GITRL is expressed on APC and is downregulated following activation J. Immunol. 173:5008, 2004
  27. 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
  28. 32. Nat. Rev. Immunol. 6:613, 2006 GITR may play a role in costimulation
  29. 33. CD103 (an integrin) is necessary for suppression of colitis
  30. 34. CD103 expression on DCs is required for suppression of colitis
  31. 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
  32. 37. CTLA-4 -/- mice make normal #s of T regs Eur J Immunol. 2004 34:2996-3005 .
  33. 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 .
  34. 39. CD4 cells from WT CD4 cells from TKO
  35. 42. Production of active TGF-  a very complex cytokine Annu. Rev. Immunol. 16:137, 1998
  36. 44. TGF-  induces T regs Can suppress Express FoxP3 J. Exp Med. 198:1875. 2003
  37. 46. Nature. 2002 420:502-7. T regs in Leishmania- infected mice Present in lesions Secrete IL-10 Suppressor function
  38. 47. T regs in infectious disease Nature. 2002 420:502-7.
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