Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 20, Pages E4651-E4660Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720409115
Keywords
T lymphocytes; T cell receptor; adaptive immune response; branched N-glycosylation; intestinal inflammation
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Funding
- Portuguese Foundation for Science and Technology (FCT)
- Norte Portugal Regional Programme (NORTE 2020) under PORTUGAL 2020 through European Regional Development Fund [NORTE-01-0145-FEDER-000029]
- Fundo Europeu de Desenvolvimento Regional (FEDER) funds through COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020
- Portuguese funds through FCT [POCI-01/ 0145-FEDER-016601, PTDC/DTP-PIC/0560/2014]
- European Crohn's and Colitis Organization (ECCO)
- Broad Medical Research Program at the Crohn's and Colitis Foundation of America
- Portuguese Group of Study in IBD (GEDII)
- FCT [PD/BD/105982/2014, SFRH/BPD/91623/2012, SFRH/ BD/110148/2015]
- CHP
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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.
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