THE THRESHOLD FOR AUTOIMMUNE T-CELL KILLING IS INFLUENCED BY B7-1

The concept that naive CD4(+) and CD8(+) T cells require co-stimulator y signals for activation and proliferation is well documented. Less cl ear is the need for co-stimulation during the effector phase of the T cell response. Here we examined the influence of B7-1 (CD80) during th e effector phase of an autoimmune response to pancreatic islets using transgenic mouse lines which expressed B7-1 in either all or only some of their beta cells (''confluent'' or ''patchy'' RIP-B7-1 mice). Tran sgenic expression of B7-1 in normal mouse islets that co-expressed the pro-inflammatory cytokine, IL-2, resulted in early spontaneous autoim munity. Islets with IL-2 and ''confluent'' B7-1 expression were destro yed whereas islets with IL-2 and ''patchy'' B7-1 expression showed sel ective killing of the B7-1(+) beta cells. Islet-reactive T cells, circ ulating in the RIP-B7-1/IL-2 mice, rejected syngeneic islet grafts, bu t only if these expressed B7-1. Introduction of the B7-1 transgene int o the nonobese diabetic (NOD) genetic background likewise resulted in early spontaneous autoimmunity, but splenocytes from the diabetic anim als could only transfer diabetes to NOD scid recipients that expressed B7-1 on their beta cells. In both these transgenic models, therefore, islet destruction required continuous B7-1 expression by target beta cells. Thus, although the normal repertoire contains T cells with pote ntial islet reactivity, these T cells remain harmless because parenchy mal cells like the beta cell cannot normally express 87-1. Our results also have implications for tumor immunotherapy in that the ability of T cells to kill poorly immunogenic targets may be dependent upon B7-1 expression by the target cell itself.