Regulation of the Immune Response

April 23, 2008Penny Morel

4-0343, morel@pitt.edu

Levels of Immune regulation

• Homeostatic control• Peripheral tolerance to self antigens

• Initiation and termination of immune responses to foreign antigens

• Immunological memory

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

Nature Immunol. 1:107, 2000

Nature Reviews Immunology 2, 547-556 (2002)

Peripheral T cell tolerance

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

• Suppression

Figure 13-12

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

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• 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

Science 280:243. 1998

Immunity 16:23, 2002

Science 280:243. 1998

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

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

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 suppressionGITR -/-

None

25+

GITR -/-

25-

Filled symbolsAnti-GITR Ab

25+ and 25-

J. Immunol. 173:5008, 2004

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 requiresB7 molecules. Lack of stimulation can be reversed byadding anti-CD28 mAb.

J. Exp. Med. 189:435, 1999

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 34:2996-3005.

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 regsCan suppressExpress FoxP3

J. Exp Med. 198:1875. 2003

Nature. 2002 420:502-7.

T regs in Leishmania-infected micePresent in lesionsSecrete IL-10Suppressor function

T regs in infectious diseaseNature. 2002 420:502-7.