MICE EXPRESSING BOTH B7-1 AND VIRAL GLYCOPROTEIN ON PANCREATIC BETA-CELLS ALONG WITH GLYCOPROTEIN-SPECIFIC TRANSGENIC T-CELLS DEVELOP DIABETES DUE TO A BREAKDOWN OF T-LYMPHOCYTE UNRESPONSIVENESS

T lymphocytes have been implicated in the onset of many autoimmune dis eases; however, the mechanisms underlying T-cell activation toward sel f antigens are poorly understood. To study whether T-lymphocyte costim ulation can overcome the immunologic unresponsiveness observed in an i n vivo model, we have created transgenic mice expressing the costimula tory mouse molecule B7-1, a ligand for the CD28 receptor, on pancreati c beta cells. We now report that triple-transgenic mice expressing bot h B7-1 and a viral glycoprotein on their beta cells, along with T cell s expressing the viral-glycoprotein-specific transgenic T-cell recepto r, all develop insulitis (lymphocytic infiltration of the pancreatic i slets) and diabetes. In striking contrast, the T cells in double-trans genic mice expressing the same viral glycoprotein (but no B7) on their pancreatic beta cells and the transgenic T-cell receptor on their T c ells, reported earlier, remain indifferent to the glycoprotein-express ing beta cells. In fact, all three transgenes are required to initiate immune-mediated destruction of the beta cells. Mice expressing any of the transgenes alone, or any two in combination, maintain normal isle t architecture and never spontaneously develop insulitis or diabetes. Our results show that aberrant B7 expression on peripheral tissues may play an important role in the activation of self-reactive T cells and further suggest that abnormal expression of costimulatory receptors m ay be involved in various T-cell-mediated autoimmune diseases.