The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1047/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 7, April 6, 1998 1047-1056

Articles

{alpha}/β–T Cell Receptor (TCR)+CD4–CD8– (NKT) Thymocytes Prevent Insulin-dependent Diabetes Mellitus in Nonobese Diabetic (NOD)/Lt Mice by the Influence of Interleukin (IL)-4 and/or IL-10

Kirsten J.L. Hammond, Lynn D. Poulton, Linda J. Palmisano, Pablo A. Silveira, Dale I. Godfrey, and Alan G. Baxter

From the Autoimmunity Research Group, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia

We have previously shown that nonobese diabetic (NOD) mice are selectively deficient in {alpha}/β-T cell receptor (TCR)+CD4–CD8– NKT cells, a defect that may contribute to their susceptibility to the spontaneous development of insulin-dependent diabetes mellitus (IDDM). The role of NKT cells in protection from IDDM in NOD mice was studied by the infusion of thymocyte subsets into young female NOD mice. A single intravenous injection of 106 CD4–/lowCD8– or CD4–CD8– thymocytes from female (BALB/c x NOD)F1 donors protected intact NOD mice from the spontaneous onset of clinical IDDM. Insulitis was still present in some recipient mice, although the cell infiltrates were principally periductal and periislet, rather than the intraislet pattern characteristic of insulitis in unmanipulated NOD mice. Protection was not associated with the induction of "allogenic tolerance" or systemic autoimmunity. Accelerated IDDM occurs after injection of splenocytes from NOD donors into irradiated adult NOD recipients. When {alpha}/β-TCR+ and {alpha}/β-TCR– subsets of CD4–CD8– thymocytes were transferred with diabetogenic splenocytes and compared for their ability to prevent the development of IDDM in irradiated adult recipients, only the {alpha}/β-TCR+ population was protective, confirming that NKT cells were responsible for this activity. The protective effect in the induced model of IDDM was neutralized by anti–IL-4 and anti–IL-10 monoclonal antibodies in vivo, indicating a role for at least one of these cytokines in NKT cell-mediated protection. These results have significant implications for the pathogenesis and potential prevention of IDDM in humans.

Address correspondence to A.G. Baxter, Autoimmunity Research Group, Centenary Institute of Cancer Medicine and Cell Biology, Locked bag No. 6, Newtown NSW 2042, Australia. Phone: 61-2-95656174; Fax: 61-2-95656103; E-mail: a.baxter{at}centenary.usyd.edu.au

The current address of K.J.L. Hammond and D.I. Godfrey is Monash Medical School Department of Pathology and Immunology, Commercial Rd., Prahran VIC 3181, Australia.

1 Abbreviations used in this paper: APC, allophycocyanin; BCG, bacillus Calmette-Guerin; DN, double negative; IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic; RT, room temperature.


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