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

Publication . Dias, Ana M.; Correia, Alexandra; Pereira, Márcia S.; Almeida, Catarina R.; Alves, Inês; Pinto, Vanda; Catarino, Telmo A.; Mendes, Nuno; Leander, Magdalena; Oliva-Teles, MT; Maia, Luís; Delerue-Matos, Cristina; Taniguchi, Naoyuki; Lima, Margarida; Pedroto, Isabel; Marcos-Pinto, Ricardo; Lago, Paula; Reis, Celso A.; Vilanova, Manuel; Pinho, Salomé S.

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.

2018-04Journal article

Open access