HIGH-DENSITY INSULIN RECEPTOR-POSITIVE T-LYMPHOCYTES FROM NONOBESE DIABETIC MICE TRANSFER INSULITIS AND DIABETES

In the nonobese diabetic mouse, insulin-dependent diabetes is an autoi mmune disease characterized by T cell-mediated invasion and destructio n of pancreatic islet beta cells. The importance of insulin receptor ( IR) expression in the pathogenesis of diabetes was examined, since it has been shown that the IR is a chemotactic receptor capable of direct ing cell movement in response to insulin, Using polyclonal antisera to the IR, phenotypic analysis of purified splenic T cells from diabetic mice showed that about 15% of T cells expressed high density IR (IR(h igh)). In addition, IR(high) T cells were already a dominant phenotype in the insulitis of young prediabetic mice, To determine the ability of IR(high) T cells to transfer diabetes, cells were sorted by flow cy tometry before adoptive transfer into young (6- to 8-wk-old) nondiabet ic irradiated nonobese mice. Transfer of as few as 3 x 10(6) purified IR(high) T cells alone resulted in rapid onset of insulitis and diabet es, and IR(high)-depleted T cells were essentially unable to passage e ither insulitis or diabetes. The adoptive transfer of disease was not due to the transfer of activated cells, since removal of IL-2R(+) or t ransferrin R(+) cells did not alter diabetes transfer. Therefore, IR(h igh) T cells are aggressively diabetogenic, suggesting that increased IR expression may provide a mechanism for delivering potentially autor eactive T cells to the islet, regardless of their activation state.