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* Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris V, Hôpital Necker, and
Hôpital Européen Georges Pompidou, Service d’Anatomie et Cytologie Pathologiques, Paris, France;
Institut National de la Santé et de la Recherche Médicale, Unité 589, Institut L. Bugnard, Centre Hospitalier et Universitaire Rangueil, Toulouse, France; and
Institut National de la Santé et de la Recherche Médicale, Unité 620, Faculté de Médecine-Pharmacie, Université de Rennes 1, Rennes, France
IL-12 is essential for invariant NKT (iNKT) cells because it can maintain a functionally active population and promote a cytokine profile that is assumed to be mainly of the pro-Th1 type. We used the murine concanavalin A (Con A)-induced hepatitis model, in which iNKT cells, IL-12, IL-4, and IFN-
are equally requisite, to reevaluate this issue. We demonstrate that IL-12 interacts directly with iNKT cells, contributes to their recruitment to the liver, and enhances their IL-4 production, which is essential for disease onset. IL-12-deficient mice were less susceptible to experimental hepatitis and their iNKT cells produced less IL-4 than their wild-type counterpart. A normal response could be restored by IL-12 injection, revealing its importance as endogenous mediator. In accordance with this observation, we found that iNKT cells expressed the IL-12R constitutively, in contrast to conventional T cells. Furthermore, the physiological relevance of our data is supported by the lower susceptibility to disease induction of NOD mice, known for their inherent functional and numerical abnormalities of iNKT cells associated with decreased iNKT cell-derived IL-4 production and low IL-12 secretion. Taken together, our findings provide the first evidence that IL-12 can enhance the immune response through increased IL-4 production by iNKT cells, underscoring once more the functional plasticity of this subset.
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 funding from the Centre National de la Recherche Scientifique, University René Descartes-Paris V, the Chancellerie des Universités de Paris (legs Poix), and from Institut National de la Santé et de la Recherche Médicale, Programme National de Recherche sur le Diabète 2004, and by fellowships from the Association pour la Recherche sur le Cancer (to R.Z.), the Académie de Médecine (to R.Z.), the Fondation pour la Recherche Médicale (to L.M.A.) and the Association Française des Diabétiques (to A.A.).
2 Address correspondence and reprint requests to Dr. André Herbelin, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Hôpital Necker, 161 rue de Sèvres, 75783 Paris Cedex 15, France. E-mail address: herbelin{at}necker.fr
3 Abbreviations used in this paper: iNKT, invariant NKT; ALT, alanine transaminase; MNC, mononuclear cell; 
-GalCer, -galactosylceramide.
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