Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity

Abstract

It is widely accepted that T cells play an important role in the destruction of β cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perform-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the β cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP specific T cell response resulting in rapid development of diabetes. We report here that in perform-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation of LCMV-GP-specific T cells. Deletion of vβ61 T cells in Mls-1a perforin deficient mice and the activation of LCMV- GP specific T cells m perform-deficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perform gone and that there is no fundamental difference between the T cell repertoires of normal control and perform-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR transgenic perform-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without tile development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insulitis but is critical for the destruction of β cells in the later phase of the disease process. Other mechanism or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently reduce diabetogenic β cell damage.