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J. Biol. Chem., Vol. 282, Issue 27, 20027-20035, July 6, 2007

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Control of T Cell-mediated Autoimmunity by Metabolite Flux to N-Glycan Biosynthesis^*

Ani Grigorian¹, Sung-Uk Lee¹, Wenqiang Tian, I.-Ju Chen, Guoyan Gao, Richard Mendelsohn^¶, James W. Dennis^¶||, and Michael Demetriou²

From the Departments of Neurology and Microbiology and Molecular Genetics, University of California, Irvine, California 92697, ^¶Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, and ^||Department of Molecular and Medical Genetics, University of Toronto, Ontario M5G 1L5, Canada

Autoimmunity is a complex trait disease where the environment influences susceptibility to disease by unclear mechanisms. T cell receptor clustering and signaling at the immune synapse, T cell proliferation, CTLA-4 endocytosis, T_H1 differentiation, and autoimmunity are negatively regulated by 1,6GlcNAc-branched N-glycans attached to cell surface glycoproteins. 1,6GlcNAc-branched N-glycan expression in T cells is dependent on metabolite supply to UDP-GlcNAc biosynthesis (hexosamine pathway) and in turn to Golgi N-acetylglucosaminyltransferases Mgat1, -2, -4, and -5. In Jurkat T cells, 1,6GlcNAc-branching in N-glycans is stimulated by metabolites supplying the hexosamine pathway including glucose, GlcNAc, acetoacetate, glutamine, ammonia, or uridine but not by control metabolites mannosamine, galactose, mannose, succinate, or pyruvate. Hexosamine supplementation in vitro and in vivo also increases 1,6GlcNAc-branched N-glycans in naïve mouse T cells and suppresses T cell receptor signaling, T cell proliferation, CTLA-4 endocytosis, T_H1 differentiation, experimental autoimmune encephalomyelitis, and autoimmune diabetes in non-obese diabetic mice. Our results indicate that metabolite flux through the hexosamine and N-glycan pathways conditionally regulates autoimmunity by modulating multiple T cell functionalities downstream of 1,6GlcNAc-branched N-glycans. This suggests metabolic therapy as a potential treatment for autoimmune disease.

Received for publication, March 5, 2007 , and in revised form, April 19, 2007.

^* This research was supported by grants from Canadian Institutes for Health Research (to J. W. D.) and from the National Multiple Sclerosis Society, the Juvenile Diabetes Research Foundation, the Wadsworth Foundation, and NIAID, National Institutes of Health (to M. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Depts. of Neurology and Microbiology and Molecular Genetics, University of California, 250 Sprague Hall, Irvine, CA 92697. Tel.: 949-824-9775; Fax: 949-824-9847; E-mail: mdemetri{at}uci.edu.

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