Development o f Insulitis without Diabetes in Transgenic Mice Lacking Perforin-dependent Cytotoxicity By David K~igi,*

It is widely accepted that T cells play an important role in the destruction of [3 cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perforin-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the 13 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 perforin-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation ofLCMV-GP-specific T cells. Deletion o fv~6 + T cells in Mls-1 a perforin-deficient mice and the activation of LCMV-GP-specific T cells in perforindeficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific T C R transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4 + and CD8 + T cells without the development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insuhtis but is crucial for the destruction of [3 cells in the later phase of the disease process. Other mechanisms or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently induce diabetogenic 13 cell damage.