Mechanisms of human immune modulation by oral N-acetylglucosamine

University Of California-Irvine, Irvine CA

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Abstract

DESCRIPTION (provided by applicant): Our published data in mice has revealed that the simple sugar and dietary supplement N- acetylglucosamine (GlcNAc) inhibits T cell function and autoimmunity by enhancing N-glycosylation in T cells. Virtually all cell surface and secreted proteins in metazoans are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway, imparting substantial molecular information not encoded by the genome. We find that genetic, metabolic and environmental regulation of Golgi N-glycosylation controls macromolecular complexes on the cell surface to influence cell growth, differentiation and disease states. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, forming a galectin-glycoprotein lattice that controls the distributin, clustering and endocytosis of surface glycoproteins in a predictable manner. N-glyan branching deficiency induces T cell hyper-activity and spontaneous autoimmune disease in mice by enhancing T cell receptor clustering/signaling, reducing surface retention of the growth inhibitors CTLA-4 and TGF-ßRI/II and promoting differentiation into pro-inflammatory TH1/TH17 cells. In humans, multiple genetic and environmental risk factors for Multiple Sclerosis (MS) converge to dysregulate N- glycosylation and CTLA-4 surface retention. These include genetic variants in interleukin-7 receptor-?, interleukin-2 receptor-?, MGAT1, MGAT5 and CTLA-4 as well as Vitamin D3 and metabolic production of UDP-GlcNAc, the substrate for MGAT1 and MGAT5. Rescuing N-glycan branching deficiency in T cells in vitro and in vivo by metabolically increasing UDP-GlcNAc with the dietary supplement N-acetylglucosamine (GlcNAc), suppresses T cell growth, enhances CTLA-4 and TGF-ßRI/II surface expression, blocks TH1/TH17 differentiation, inhibits MS and autoimmune diabetes models and rescues N-glycan branching deficiency induced by MS genetic risk factors. Therapeutic supplementation to N-glycan biosynthesis with GlcNAc may provide a personalized medicine approach to suppress an underlying molecular defect promoting human autoimmunity. Here we propose to examine whether oral GlcNAc in humans enhances N-glycan branching to suppress T cell function and induce immune deviation, focusing on individuals with genetic polymorphisms that promote MS and down-regulate N-glycan branching in T cells. Specific Aim 1 examines whether in vitro GlcNAc regulates hypomorphic N-glycan branching in male vs female human T cells to suppress pro- autoimmune TH1/TH17 cells while enhancing anti-autoimmune T regulatory cells. Specific Aim 2 examines whether oral GlcNAc enhances N-glycan branching to suppress pro-autoimmune TH1/TH17 responses while enhancing anti-autoimmune T regulatory cells in MS patients with genetic defects in N-glycosylation.