IFN-alpha induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B7.2.
Insulin-dependent diabetes is an autoimmune disease characterized by the loss of the insulin-producing beta cells and the appearance of autoreactive (anti-islet) T cells. The mechanism by which these autoimmune T cells become activated has not been resolved. We demonstrate that the expression of IFN-alpha by the pancreatic beta cells leads to the development of CD4+ T cells that proliferate in the presence of islet Ags. These autoreactive T cells have a Th1 phenotype and are able to lyse islet cells, possibly through an indirect, cytokine-mediated mechanism. We also demonstrate that the pancreatic infiltrating leukocytes in the transgenic mice express increased levels of 87.2 and ICAM-1 and that IFN-alpha can directly induce these two costimulatory molecules on nontransgenic splenic APCs. Treatment of the transgenic mice with Abs against these costimulatory molecules demonstrated that B7.2 is essential for the induction of autoreactive T cells, whereas ICAM-1 contributes to but is not essential for the formation of these autoreactive cells. As B7.2 and ICAM-1 are able to synergize to provide costimulatory signals to naive T cells under conditions of limiting Ag, we propose that IFN-alpha expression normally contributes to the development of an anti-viral cellular immune response, but that uncontrolled expression of this cytokine will induce autoimmunity.
Chakrabarti
D
D
Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
Hultgren
B
B
Stewart
T A
TA
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000187:drug effects; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D051940:B7-2 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1