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Invariant NKT Cells Exacerbate Type 1 Diabetes Induced by CD8 T Cells¹

Thibault Griseri^*, Lucie Beaudoin^*, Jan Novak^*, Lennart T. Mars, Françoise Lepault^*, Roland Liblau and Agnès Lehuen^2,*

^* Institut National de la Santé et de la Recherche Médicale (INSERM) U561, Hôpital Cochin/Saint Vincent de Paul, Paris, France; and INSERM U563, Hôpital Purpan, Toulouse, France

Invariant NKT (iNKT) cells have been implicated in the regulation of autoimmune diseases. In several models of type 1 diabetes, increasing the number of iNKT cells prevents the development of disease. Because CD8 T cells play a crucial role in the pathogenesis of diabetes, we have investigated the influence of iNKT cells on diabetogenic CD8 T cells. In the present study, type 1 diabetes was induced by the transfer of CD8 T cells specific for the influenza virus hemagglutinin into recipient mice expressing the hemagglutinin Ag specifically in their pancreatic cells. In contrast to previous reports, high frequency of iNKT cells promoted severe insulitis and exacerbated diabetes. Analysis of diabetogenic CD8 T cells showed that iNKT cells enhance their activation, their expansion, and their differentiation into effector cells producing IFN-. This first analysis of the influence of iNKT cells on diabetogenic CD8 T cells reveals that iNKT cells not only fail to regulate but in fact exacerbate the development of diabetes. Thus, iNKT cells can induce opposing effects dependent on the model of type 1 diabetes that is being studied. This prodiabetogenic capacity of iNKT cells should be taken into consideration when developing therapeutic approaches based on iNKT cell manipulation.

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