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Metabolic control of T cell immune response through glycans in inflammatory bowel disease

Significance Our findings demonstrate that metabolic supplementation of mucosal T cells, isolated from patients with active ulcerative colitis (UC), with N-acetylglucosamine (GlcNAc) leads to the enhancement of branched N-glycosylation on the T cell receptor, which was associated with the control of T cell activation and function. These results were validated in “glycoengineered” mouse models with severe colitis. Overall, our results open new avenues for a targeted-specific therapy in inflammatory bowel disease (IBD). The therapeutic use of GlcNAc (either alone or in combination with other antiinflammatory therapies) represents a simple immunomodulatory strategy in IBD, with absence of side effects, low costs, and the possibility of being used as a simple rescue therapy to avoid unnecessary toxic effects and step-up therapies in IBD. Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5−/−, MGAT5+/−) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.