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

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.
We thank Dr. Hiroaki Korekane and Fumi (RIKEN) for support in preparation of the fluorescent oligosaccharide acceptor substrate. We thank Dr. Michael Pierce for kindly providing the MGAT5 knockout mice. We also thank Paula Paíga (REQUIMTE/LAQV) for technical support with the HPLC system. The Institute of Molecular Pathology and Immunology of the University of Porto integrates the i3S research unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT). This article is a result of the project NORTE-01-0145-FEDER-000029, supported by the Norte Portugal Regional Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund. This work was also funded by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through the FCT in the framework of the project (POCI-01/0145-FEDER-016601 and PTDC/DTP-PIC/0560/2014). S.S.P. acknowledges the European Crohn’s and Colitis Organization (ECCO) for ECCO Grant 2017, the Broad Medical Research Program at the Crohn’s and Colitis Foundation of America, and the Portuguese Group of Study in IBD (GEDII) for funding. A.M.D. [PD/BD/105982/2014], A.C. [SFRH/BPD/91623/2012], and M.S.P. [SFRH/BD/110148/2015] received funding from the FCT. M. Lima thanks the CHP for the research support.