Regulation of the Immune Response

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Regulation of the Immune Response

• April 4, 2007
• Penny Morel
• 4-0343, morel_at_pitt.edu

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Levels of Immune regulation

• Homeostatic control
• Peripheral tolerance to self antigens
• Initiation and termination of immune responses to
  foreign antigens
• Immunological memory

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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

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Nature Immunol. 1107, 2000
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Nature Reviews Immunology 2, 547-556 (2002)
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Peripheral T cell tolerance

• Immune privilege
• Anergy
• Deletion Activation induced cell death
• Suppression

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Figure 13-12
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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

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Peripheral Self Tolerance
Nature Rev. Immunol. 211, 2002
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Nature Rev. Immunol. 211, 2002
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Nature Rev. Immunol. 211, 2002
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DC in steady state induce tolerance
Proc Natl Acad Sci U S A 2002 99351-8
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DC activation is controlled at multiple levels.
Annu Rev Immunol. 21685, 2003
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33D1 mAb recognizes DCIR2
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How is peripheral tolerance broken?
Nature Rev. Immunol. 211, 2002
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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

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Immunity 13419, 2000
AICD Cells lose survival signals Susceptible to
Fas-mediated death Enhanced by IL-2?
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Science 280243. 1998
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Science 280243. 1998
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Regulatory/suppressor T cells

• CD4 CD25 CD45RBlo CD62L suppressor T cells
• Regulatory T cells in mucosal surfaces
• Tr1 cells
• CD8 CD28- suppressor cells in human

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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-2Rb -/- 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

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IL-2 is required for development and maintenance
of Tregs
J Exp Med. 2005 201723-35
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J Exp Med. 2005 201723-35
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Immunity 12431, 2000
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Immunity 12431, 2000
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T cell transfer into A. NOD-Scid or B. CD28 -/-
mice
Immunity 12431, 2000
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GITR
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GITRL is expressed on APC and is downregulated
following activation
J. Immunol. 1735008, 2004
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GITR expression on CD25- T cells abrogates
suppression
GITR -/- None 25
GITR -/- 25- Filled symbols Anti-GITR Ab 25
and 25-
J. Immunol. 1735008, 2004
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GITR may play a role in costimulation
Nat. Rev. Immunol. 6613, 2006
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CD103 (an integrin) is necessary for suppression
of colitis
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CD103 expression on DCs is required for
suppression of colitis
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Lethal autoimmune disease in CTLA-4 -/- mice
requires B7 molecules. Lack of stimulation can be
reversed by adding anti-CD28 mAb. J. Exp. Med.
189435, 1999
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CTLA-4 -/- mice make normal s of T regs
Eur J Immunol. 2004 342996-3005.
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In wild type mice CTLA-4 is important for in
vitro suppression
Eur J Immunol. 2004 342996-3005.
CTLA-4 -/- T regs can still suppress
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CD4 cells from WT CD4 cells from TKO
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Production of active TGF-???a very complex
cytokine
Annu. Rev. Immunol. 16137, 1998
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TGF-b induces T regs Can suppress Express
FoxP3 J. Exp Med. 1981875. 2003
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T regs in Leishmania- infected mice Present in
lesions Secrete IL-10 Suppressor function
Nature. 2002 420502-7.
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T regs in infectious disease
Nature. 2002 420502-7.
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