A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: Possible role of membrane TNF

Double transgenic mice [rat insulin promoter (RIP)-tumor necrosis factor (T NF) and RIP-CD80] whose pancreatic beta cells release TNF and bear CD80 all develop an acute early (6 wk) and lethal diabetes mediated by CD8 T cells. The first ultrastructural changes observed in beta cells, so far unreporte d, are focal lesions of endoplasmic reticulum swelling at the points of con tact with islet-infiltrating lymphoblasts, followed by cytoplasmic, but not nuclear, apoptosis, Such double transgenic mice were made defective in eit her the perforin, Fas, or TNF pathways. Remarkably, diabetes was found to b e totally independent of perforin and Fas. Mice lacking TNF receptor (TNFR) II had no or late diabetes, but only a minority had severe insulitis, Mice lacking the TNF-lymphotoxin (LT alpha) locus (whose sole source of TNF are the beta cells) all had insulitis comparable to that of nondefective mice, but no diabetes or a retarded and milder form, with lesions suggesting dif ferent mechanisms of injury. Because both TNFR II and TNF-LT alpha mutation s have complex effects on the immune system, these data do not formally inc riminate membrane TNF as the major T cell mediator of this acute autoimmune diabetes; nevertheless, in the absence of involvement of the perforin or F as cytotoxic pathways, membrane TNF appears to be the likeliest candidate.