OVEREXPRESSION OF NATURAL-KILLER T-CELLS PROTECTS V-ALPHA-14-J-ALPHA-281 TRANSGENIC NONOBESE DIABETIC MICE AGAINST DIABETES

Progression to destructive insulitis in nonobese diabetic (NOD) mice i s linked to the failure of regulatory cells, possibly involving T help er type 2 (Th2) cells. Natural killer (NK) T cells might be involved i n diabetes, given their deficiency in NOD mice and the prevention of d iabetes by adoptive transfer alpha/beta double-negative thymocytes. He re, we evaluated the role of NK T cells in diabetes by using transgeni c NOD mice expressing the T cell antigen receptor (TCR) alpha chain V alpha 14-J alpha 281 characteristic of NK T cells. Precise identificat ion of NK1.1(+) T cells was based on out-cross with congenic NK1.1 NOD mice. AU six transgenic lines showed, to various degrees, elevated nu mbers of NK1.1(+) T cells, enhanced production of interleukin (IL)-4, and increased levels of serum immunoglobulin E. Only the transgenic li nes with the largest numbers of NK T cells and the most vigorous burst of IL-4 production were protected from diabetes. Transfer and cotrans fer experiments with transgenic splenocytes demonstrated that V alpha 14-J alpha 281 transgenic NOD mice, although protected from overt diab etes, developed a diabetogenic T cell repertoire, and that NK T cells actively inhibited the pathogenic action of T cells. These results ind icate that the number of NK T cells strongly influences the developmen t of diabetes.