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Diabetes 55:1163-1170, 2006
DOI: 10.2337/diabetes.55.04.06.db05-0908
© 2006 by the American Diabetes Association
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Genetic and Functional Analysis of the Nkt1 Locus Using Congenic NOD Mice

Improved V{alpha}14-NKT Cell Performance but Failure to Protect Against Type 1 Diabetes

Ana-Claudia Rocha-Campos1, Rahma Melki2, Ren Zhu1, Nathalie Deruytter2, Diane Damotte2,3, Michel Dy1, André Herbelin1, and Henri-Jean Garchon2

1 Centre National de Recherche (CNRS) Unité Mixte de Recherche (UMR) 8147, Université Paris 5, Paris, France
2 Institut National de la Santé et de la Recherche Médicale (INSERM) U580, Université Paris 5, Paris, France
3 Hôpital Européen George Pompidou, Paris, France

Address correspondence and reprint requests to Henri-Jean Garchon, INSERM U580, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: garchon{at}necker.fr. Or André Herbelin, CNRS INSERM 8147, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: herbelin{at}necker.fr

Abbreviations: APC, allophycocyanin; ELISA, enzyme-linked immunosorbent assay; FITC, fluorescein isothiocyanate; {alpha}-GalCer, {alpha}-galatosylceramide; IFN-{gamma}, {gamma}-interferon; IL, interleukin; iNKT cell, invariant natural killer T-cell; mAb, monoclonal antibody; SLAM, signaling lymphocytic activation molecule; TCR, T-cell antigen receptor

Defective invariant natural killer T-cells (iNKT cells) have been implicated in the etiology of type 1 diabetes in nonobese diabetic (NOD) mice. In a genome scan of a cross between NOD and C57BL/6 mice, the most significant locus controlling the number of iNKT cells, referred to as Nkt1, was recently mapped to distal chromosome 1. Here, using congenic mice for this chromosomal segment, we definitively demonstrate the existence of Nkt1 and show that introgression of the C57BL/6 allele onto the NOD background improves both the number of iNKT cells and their rapid production of cytokines elicited by {alpha}-galactosylceramide treatment, explaining at least half of the difference between the NOD and C57BL/6 strains. Using new subcongenic lines, we circumscribed the Nkt1 locus to a 8.7-cM segment, between the NR1i3 and D1Mit458 markers, that notably includes the SLAM (signaling lymphocytic activation molecule) gene cluster, recently involved in murine lupus susceptibility. However, despite a significant correction of the iNKT cell defect, the Nkt1 locus did not alter the course of spontaneous diabetes in congenic mice. Our findings indicate a complex relationship between iNKT cells and autoimmune susceptibility. Congenic lines nonetheless provide powerful models to dissect the biology of iNKT cells.


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2006 by the American Diabetes Association.