T cell tolerance and autoimmunity.
CD4 T cells are the master controllers of immune responses to protein antigens, and many autoimmune diseases are thought to arise from a breakdown of immunological tolerance in CD4 cells. Peripheral tolerance in CD4 T cells is maintained by several mechanisms, including functional anergy, deletion (death) by apoptosis and suppression by regulatory T lymphocytes (Treg). Using transgenic mouse models, we have explored the roles of these mechanisms in tolerance to cell-associated tissue-restricted self-antigens and secreted systemic self-antigens. Tolerance to a membrane form of the antigen expressed in islet beta cells is maintained by Treg, which block T cell differentiation into pathogenic effectors, and by CTLA-4, which increases the activation threshold of T cells and prevents responses to the self-antigen. A systemically produced soluble form of the antigen induces rapid T cell anergy followed by deletion. The induction of anergy does not require either CTLA-4 or Treg, although in the absence of Treg tolerance can be broken more readily by potent immunogenic signals. Encounter with circulating antigen in T cells induces a state of antigen receptor "desensitization" that is associated with a block in proximal receptor-triggered signals. Thus, different mechanisms play dominant roles in T cell tolerance to different types of self-antigens.
Abbas
Abul K
AK
Department of Pathology, University of California San Francisco School of Medicine, 505 Parnassus Avenue, Suite M590, San Francisco, CA 94143-0511, USA. aabbas@itsa.ucsf.edu
Lohr
Jens
J
Knoechel
Birgit
B
Nagabhushanam
Vijaya
V
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell