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Activation of Invariant NKT Cells Ameliorates Experimental Ocular Autoimmunity by A Mechanism Involving Innate IFN- Production and Dampening of the Adaptive Th1 and Th17 Responses¹

Rafael S. Grajewski^2,3,*, Anna M. Hansen^2,*, Rajeev K. Agarwal^4,*, Mitchell Kronenberg, Stephane Sidobre, Shao Bo Su^5,*, Phyllis B. Silver^*, Moriya Tsuji, Richard W. Franck, Anne P. Lawton, Chi-Chao Chan^* and Rachel R. Caspi^6,*

^* Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016; and Hunter College of the City University of New York, New York, NY 10021

Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with -C-GalCer, which induces a strong IFN- but only a weak IL-4 production by iNKT cells, in contrast to the ligands -GalCer (both IFN- and IL-4) and OCH (primarily IL-4). The protective effect of -C-GalCer was associated with a reduction of adaptive Ag-specific IFN- and IL-17 production and was negated by systemic neutralization of IFN-. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN- and a consequent dampening of the Th1 as well as the Th17 effector responses.

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 National Institutes of Health Intramural funding.

² R.S.G. and A.M.H. contributed equally to this study.

³ Current address: Würzburg University, University Eye Hospital, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany.

⁴ Current address: Organ Systems Branch, Office of Centers, Training and Resources, Office of the Director, National Cancer Institute, National Institutes of Health, 6116 Executive Boulevard, Suite 7006, Rockville, MD 20852.

⁵ Current address: Institute of Inflammation and Immune Diseases, Shantou University Medical College, 22 Xin Ling Road, Shantou City, 515041, People’s Republic of China.

⁶ Address correspondence and reprint requests to Dr. Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, 10/10n222, Bethesda, MD 20892-1857. E-mail address: rcaspi{at}helix.nih.gov

⁷ Abbreviations used in this paper: iNKT, invariant NKT cell; EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; -GalCer, -galactosylceramide; OCH, (2s,3s,4r)-1-O-(-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol); ACAID, anterior chamber-associated immune deviation; WT, wild type; KO, knockout; EAE, experimental autoimmune encephalomyelitis.

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