DEVELOPMENT OF INSULITIS WITHOUT DIABETES IN TRANSGENIC MICE LACKING PERFORIN-DEPENDENT CYTOTOXICITY

It is widely accepted that T cells play an important role in the destr uction of beta cells leading to autoimmune type I diabetes, but the in volved effector mechanisms have remained unclear. We addressed this is sue by testing the role of perforin-dependent cytotoxicity in a diseas e model involving transgenic mice expressing glycoprotein of lymphocyt ic choriomeningitis virus (LCMV-GP) in the beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP-spec ific T cell response resulting in rapid development of diabetes. We re port here that in perforin-deficient LCMV-GP transgenic mice, LCMV inf ection failed to induce diabetes despite the activation of LCMV-GP-spe cific T cells. Deletion of v beta 6(+) T cells in Mls-1(a) perforin-de ficient mice and the activation of LCMV-GP-specific T cells in perfori n-deficient LCMV-GP transgenic mice, however, indicated that thymic to lerance induction by negative selection was not affected by the disrup tion of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficien t mice. In addition, adoptive transfer of LCMV-GP-speciGc TCR transgen ic perforin-deficient T cells activated by LCMV-GP recombinant vaccini a virus led to marked insulitis with infiltration of CD4(+) and CD8(+) T cells without the development oi diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiatio n of insulitis but is crucial for the destruction of beta cells in the later phase of the disease process. Other mechanisms or soluble facto rs present in the inflammatory islet infiltrate apparently lack the ab ility to efficiently induce diabetogenic beta cell damage.