Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent

Although transgenic mice expressing murine B7-1 (mCD80) on their pancreatic beta cells under the rat insulin-1 promoter (RIPmCD80(+) mice) rarely deve lop spontaneous beta cell destruction and diabetes, we have previously repo rted the transgene-dependent induction of profound insulitis and lethal dia betes following multiple low dose injections of the beta cell toxin strepto zotocin (MLDS) in RIP-mCD80(+) mice. Here, we have further characterized th is MLDS-induced diabetes model using the RIP-mCD80(+) mice and now demonstr ate that disease is critically dependent on T cell signaling via CD28. Thus , although naive RTP-mCD80(+) and nontransgenic littermates have comparable gross beta cell mass, and immediately following MLDS induction the mice di splay similar degrees of insulitis and decrements in the beta cell mass, on ly transgenic mice continued to destroy their P cells and develop insulin-d ependent diabetes mellitus. Strikingly, MLDS-induced diabetes was completel y prevented in CD28-deficient mice (RIP-mCD80(+)CD28(-/-)) due to abrogatio n of leukocytes infiltrating their pancreatic islets. We further characteri zed MLDS-induced diabetes in the RIP-mCD80(+) mice by demonstrating that th e MLDS-induced lymphocytic islet infiltrate contained a substantial frequen cy of autoantigen-specific, IPN-gamma -secreting, CD8(+) T cells. We conclu de that MLDS-induced P cell, destruction and subsequent insulin-dependent d iabetes mellitus in RIP-mCD80(+) mice is T cell-mediated as it involves bot h Ag-specific recognition of self-target molecules in the inflamed pancreat ic islet (signal 1) and is CD28 costimulation dependent (signal 2). The Jou rnal of Immunology, 2001, 166: 2531-2539.