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© The Rockefeller University Press, 0022-1007/1998/11/1831/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1831-1839

Articles

Overexpression of Natural Killer T Cells Protects V{alpha}14-J{alpha}281 Transgenic Nonobese Diabetic Mice against Diabetes

Agnès Lehuen*, Olivier Lantz*, Lucie Beaudoin*, Véronique Laloux*, Claude Carnaud*, Albert Bendelac{ddagger}, Jean-François Bach*, and Renato C. Monteiro*

From * INSERM U 25, Hôpital Necker, 75743 Paris, France; and the {ddagger} Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

Progression to destructive insulitis in nonobese diabetic (NOD) mice is linked to the failure of regulatory cells, possibly involving T helper type 2 (Th2) cells. Natural killer (NK) T cells might be involved in diabetes, given their deficiency in NOD mice and the prevention of diabetes by adoptive transfer of {alpha}/β double-negative thymocytes. Here, we evaluated the role of NK T cells in diabetes by using transgenic NOD mice expressing the T cell antigen receptor (TCR) {alpha} chain V{alpha}14-J{alpha}281 characteristic of NK T cells. Precise identification of NK1.1+ T cells was based on out-cross with congenic NK1.1 NOD mice. All six transgenic lines showed, to various degrees, elevated numbers of NK1.1+ T cells, enhanced production of interleukin (IL)-4, and increased levels of serum immunoglobulin E. Only the transgenic lines with the largest numbers of NK T cells and the most vigorous burst of IL-4 production were protected from diabetes. Transfer and cotransfer experiments with transgenic splenocytes demonstrated that V{alpha}14-J{alpha}281 transgenic NOD mice, although protected from overt diabetes, developed a diabetogenic T cell repertoire, and that NK T cells actively inhibited the pathogenic action of T cells. These results indicate that the number of NK T cells strongly influences the development of diabetes.

Key Words: nonobese diabetic • type 1 diabetes • natural killer T cells • transgenic mice • interleukin 4

Address correspondence to Agnès Lehuen, INSERM U 25, Hôpital Necker, 161 rue de Sèvres, 75743 Paris cedex 15, France. Phone: 33-1-44-49-53-66; Fax: 33-1-43-06-23-88; E-mail: lehuen{at}necker.fr

Abbreviations used: DN, double negative; IDDM, insulin- dependent diabetes mellitus; NOD, nonobese diabetic; SA-APC, streptavidin-allophycocyanin.


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