title: Control of T Cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis.
abstract: 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(H)1 differentiation, and autoimmunity are negatively regulated by beta1,6GlcNAc-branched N-glycans attached to cell surface glycoproteins. Beta1,6GlcNAc-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, beta1,6GlcNAc-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 beta1,6GlcNAc-branched N-glycans in naïve mouse T cells and suppresses T cell receptor signaling, T cell proliferation, CTLA-4 endocytosis, T(H)1 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 beta1,6GlcNAc-branched N-glycans. This suggests metabolic therapy as a potential treatment for autoimmune disease.
authors.affiliation: Department of Neurology, University of California, Irvine, California 92697, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Grigorian
authors.forename: Sung-Uk
authors.initials: SU
authors.lastname: Lee
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Tian
authors.forename: I-Ju
authors.initials: IJ
authors.lastname: Chen
authors.forename: Guoyan
authors.initials: G
authors.lastname: Gao
authors.forename: Richard
authors.initials: R
authors.lastname: Mendelsohn
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D006056:Golgi Apparatus / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology*; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell; D047071:beta-Glucans; D014537:Uridine Diphosphate N-Acetylglucosamine; D017351:N-Acetylglucosaminyltransferases