Cytotoxic Mechanisms Employed by Mouse T Cells to Destroy Pancreatic b-Cells

Several cytotoxic mechanisms have been attributed to T cells participating in b-cell death in type 1 diabetes. However, sensi-tivity of b-cells to these mechanisms in vitro and in vivo is likely to be different. Moreover, CD4+ and CD8+ T cells may use distinct mechanisms to cause b-cell demise that possibly involve activa-tion of third-party cytotoxic cells. We used the transfer of genet-ically modified diabetogenic T cells into normal, mutant, and bone marrow chimeric recipients to test the contribution of ma-jor cytotoxic mechanisms in b-cell death. We found that 1) the killing of b-cells by CD4+ T cells required activation of the recip-ient’s own cytotoxic cells via tumor necrosis factor-a (TNF-a); 2) CD8+ T-cell cytotoxic mechanisms destroying b-cells were lim-ited to perforin and Fas ligand, as double knockouts of these molecules abrogated the ability of T cells to cause diabetes; and 3) individual CD8+ T-cell clones chose their cytotoxic weap