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Influence of a Non-NK Complex Region of Chromosome 6 on CD4⁺ Invariant NK T Cell Homeostasis¹

David Vallois^*, Marie-Claude Gagnerault^*, Philip Avner, Ute C. Rogner, Christian Boitard^*, Kamel Benlagha^*, André Herbelin and Françoise Lepault^2,*,,¶

^* Institut National de la Santé et de la Recherche Médicale U561, Université Paris Descartes, Saint Vincent de Paul Hospital, Paris, France, Centre National de la Recherche Scientifique Unité de Recherche Associée 2578, Pasteur Institute, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, Université Paris Descartes, Faculté de Médecine, Paris, France; Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; and ^¶ Institut National de la Santé et de la Recherche Médicale U567, Paris, France

The number and function of immunoregulatory invariant NKT (iNKT) cells are genetically controlled. A defect of iNKT cell ontogeny and function has been implicated as one causal factor of NOD mouse susceptibility to type 1 diabetes. Other factors of diabetes susceptibility, such as a decrease of regulatory T cell function or an increase in TLR1 expression, are corrected in diabetes-resistant Idd6 NOD.C3H 6.VIII congenic mice. Thus, we surmised that the iNKT cell defects found in NOD mice may also be rescued in congenic mice. Unexpectedly, we found, in both the thymus and the periphery, a 50% reduction in iNKT cell number in NOD.C3H 6.VIII mice as compared with NOD mice. This reduction only affected CD4⁺ iNKT cells, and left the double negative iNKT cells unchanged. In parallel, the production of IL-4 and IFN- following -GalCer stimulation was proportionally reduced. Using three subcongenic strains, we have narrowed down the region controlling iNKT development within Idd6 (5.8 Mb) to Idd6.2 region (2.5 Mb). Idd6 region had no effect on NK cell number and in vivo cytotoxic activity. These results indicate that the role of iNKT cells in diabetes development is equivocal and more complex than initially considered. In addition, they bring strong evidence that the regulation of CD4⁺ iNKT cell production is independent from that of DN iNKT cells, and involves genes of the Idd6 locus.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Juvenile Diabetes Research Foundation International (1-2000-600), Agence Nationale de la Recherche and Association pour la Recherche sur le Diabète, and by recurrent funding from Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and Institut Pasteur. D.V. has received a fellowship from the Ministère de la Recherche.

² Address correspondence and reprint requests to Dr. Françoise Lepault, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. E-mail address: francoise.lepault{at}inserm.fr

³ Abbreviations used in this paper: DN, double negative; -GalCer, -galactosylceramide; iNKT, invariant NK T cell; Idd, insulin-dependent diabetes susceptibility locus.