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* Institut National de la Santé et de la Recherche Médicale, U-563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France;
Université Toulouse III, Paul-Sabatier, Toulouse, France;
Institut National de la Santé et de la Recherche Médicale, U-561, Hôpital Cochin-Saint Vincent de Paul, Paris, France; and
University René Descartes, Paris, France
Invariant NKT cells are CD1d-restricted T cells specific for glycolipid Ags. Their activation or transgenic enrichment abrogates the development of experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate that in NKT-enriched mice the protection from EAE is associated with the infiltration of NKT cells in the CNS and the local expression of CD1d. This indicates that the CNS acquires the potential for local glycolipid presentation when exposed to inflammatory stress, permitting the triggering of NKT cells. To address the importance of CD1d-mediated Ag presentation, we used transgenic mice that express CD1d solely in the thymus. Interestingly, enrichment of NKT cells in these mice also conferred resistance to EAE, with an efficacy indistinguishable from that of NKT-enriched CD1d-sufficient mice. This protection was due to an abrogation of the encephalitogenic Th1 and Th17 response in the spleen, revealing that endogenous glycolipid presentation is dispensable for the regulatory function of NKT cells in EAE. Moreover, abrogating extrathymic CD1d expression failed to affect both the recruitment of NKT cells and their effector phenotype. CNS-infiltrating NKT cells were characterized by a cytotoxic IFN-
highIL-4lowIL-10lowgranzyme Bhigh profile, irrespective of the local expression of CD1d. Glycolipid Ag presentation is therefore dispensable for the control of autoimmune demyelination by NKT cells, underlining the importance of alternative cognate and/or soluble factors in the control of NKT cell function.
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 the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur la Sclérose en Plaques, the Agence Nationale de la Recherche (ANR-06-MIME), the European Union (Neuropromise: SHM-CT_2005-018637), and the region Midi-Pyrénées. L.T.M. was supported by a postdoctoral fellowship from the European Union (Neuropromise). A.S.G. and J.N. were supported by doctoral fellowships from the Ministère de l’Education Nationale, de la Recherche et Technique and the Foundation pour la Recherche Médicale, respectively.
2 L.T.M. and A.-S.G. contributed equally to this work.
3 R.S.L. and A.L. contributed equally to this work as principal investigators.
4 Address correspondence and reprint requests to Dr. A. Lehuen, Institut National de la Santé et de la Recherche Médicale-U561, Hôpital Cochin/Saint Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris, France. E-mail address: lehuen{at}paris5.inserm.fr. or Dr. Roland S. Liblau, Institut National de la Santé et de la Recherche Médicale-U563, Centre de Physiopathologie de Toulouse Purpan, Centre Hospitalier Universitaire Purpan, BP 3028, 31024 Toulouse Cedex 3, France. E-mail address: rolandliblau{at}hotmail.com
5 Abbreviations used in this paper: DP, double positive; 
-GalCer, -galactosylceramide; DC, dendritic cell; DN, double negative; EAE, experimental autoimmune encephalomyelitis; HPRT, hypoxanthine phosphoribosyltransferase; MBP, myelin basic protein; MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; M
, macrophage; MS, multiple sclerosis; pLck, proximal Lck; PLP, proteolipid protein; NOD, nonobese diabetic; SP, single positive; Tg, transgenic.
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