P027 Dysregulation of T cells by N-glycosylation: a new molecular mechanism in Inflammatory Bowel Disease pathogenesis.
A. M. Dias1, T. Catarino1, R. Marcos-Pinto2, A. Correia3, M. Lima4, M. Vilanova3, P. Lago2, C. Reis1, S. S. Pinho*1
1IPATIMUP, University of Porto, Glycobiology department, Porto, Portugal, 2Porto Centre Hospital, Hospital Santo António, Gastrenterology department, Porto, Portugal, 3Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Immunology department, Porto, Portugal, 4Porto Centre Hospital, Hospital Santo António, Hematology Department, Porto, Portugal
Accumulating evidence suggests that IBD Results from an inappropriate inflammatory response in a genetically susceptible host, although the underlying molecular mechanism remain elusive. One of the major clinical gaps in IBD is the ability to predict the severity of flares and their response to treatment. It is therefore of paramount importance to characterize the underlying molecular mechanism of IBD pathogenesis in order to improve the development of novel biomarkers that help the determination of prognosis and also improve the patients´ therapeutic stratification.
Recent evidences support that T cell activity and function is tightly regulated by post-translational modifications through glycosylation     .
In this study we address whether the (dys)regulation of N-glycosylation in T cells activity and function is a major contributory factor and an yet uncovered molecular mechanism in IBD.
The evaluation of the branched N-glycosylation levels and profile of intestinal T cell receptor (TCR) were assessed in colonic biopsies from Ulcerative Colitis (UC) patients and healthy controls. The underlying molecular mechanism was assessed using ex vivo intestinal T cells from UC patients and IBD-induced mouse models. Expression alterations of the glycosyltransferase gene MGAT5 were also evaluated  .
Our Results showed that UC patients exhibit a dysregulation of GnT-V-mediated glycosylation of the TCR from intestinal lamina propria T cells. Patients with severe UC showed the most pronounced defect on N-glycan branching in mucosal T cells  .
This dysfunction of GnT-V-mediated T cells glycosylation was shown to affect T cell function and signaling, being associated with increased T cell proliferation; increased TH1 differentiation and hyperimmune response. We also showed that UC patients (with active disease) exhibit, in T lymphocytes, a reduced MGAT5 gene expression, which underlies the observed dysregulation of T cells N-glycosylation. This deficiency in T cells N-glycosylation accompanies disease severity.
Overall, this study shows a new molecular mechanism in IBD pathogenesis through T cells regulation by N-glycosylation , opening new windows of opportunity to further explore the potential applicability of this mechanism in predicting disease course and/or susceptibility
“Tcells regulation by N-glycosylation in IBD.”
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