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 t he loss of the insulin-producing beta cells and the appearance of auto reactive (anti-islet) T cells. The mechanism by which these autoimmune T cells become activated has not been resolved. We demonstrate that t he expression of IFN-alpha by the pancreatic beta cells leads to the d evelopment 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 mech anism. We also demonstrate that the pancreatic infiltrating leukocytes in the transgenic mice express increased levels of B7.2 and ICAM-1 an d 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 es sential for the induction of autoreactive T cells, whereas ICAM-1 cont ributes to but is not essential for the formation of these autoreactiv e cells. As B7.2 and ICAM-1 are able to synergize to provide costimula tory signals to naive T cells under conditions of limiting Ag, we prop ose that IFN-alpha expression normally contributes to the development of an anti-viral cellular immune response, but that uncontrolled expre ssion of this cytokine will induce autoimmunity.