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P080 Modulation of T-cell glycosylation and the control of intestinal inflammation

A. M. Dias*1, 2, A. Correia3, M. Pereira1, C. R. Almeida4, M. Lima5, 6, R. Marcos-Pinto2, 7, 8, M. Vilanova2, 3, C. A. Reis1, 2, 9, P. Lago8, 
S. S. Pinho1, 2

1Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) & i3S – Instituto de Investigação e Inovação em Saúde, Glycobiology in Cancer, Porto, Portugal, 2Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Porto, Portugal, 3Instituto de Investigação e Inovação em Saude (I3S)/Institute for Molecular and Cell Biology (IBMC), Immunobiology Group, Porto, Portugal, 4Instituto de Investigação e Inovação em Saude (I3S)/ Institute of Biomedical Engineering (INEB), NEWTherapies Group, University of Porto, Porto, Portugal, 5Centro Hospitalar do Porto , Multidisciplinary Unit for Biomedical Research (UMIB), Porto, Portugal, 6Centro Hospitalar do Porto, Haematology Department, Porto, Portugal, 7Medical Faculty, Centre for Research in HealthTechnologies and Information Systems (CINTESIS), Porto, Portugal, 8Centro Hospitalar do Porto, Department of Gastroenterology, Porto, Portugal, 9University of Porto, Medical Faculty, Porto, Portugal

Background

There is an increasing need in inflammatory bowel disease (IBD) clinical practice for the identification of precise markers that could help the selection of suitable patients, early in the disease course, for an appropriate therapy.1 We found that IBD patients display a deficiency on specific glycans attached to intestinal T-cells that accompany disease severity.2 In the present study, we evaluated the relationship between the glycosylation of intestinal T-cells and their effect in the modulation of intestinal inflammation.

Methods

We developed ex-vivo cultures of colonic T-cells isolated from ulcerative colitis (UC) patients with active disease to experimentally modulate T-cells glycosylation and evaluate the effect in the regulation of immune response. The T-cell proliferation was assessed by labelling cells with 5-(and 6)-Carboxyfluorescein diacetate succinimidyl ester (CFSE) following flow cytometry, T-cell differentiation, and cytokines expression evaluated by flow cytometry, and TCR signalling by Western blot. Additionally, we used different in-vivo mouse models of colitis displaying different glycosylation patterns, and assessed the effect of glycosylation in the control of disease severity, disease course, and intestinal inflammation.

Results

Our results on ex-vivo T-cells, showed that modulation of glycosylation of T-cells can have an effect in the suppression of T-cell immune response, namely in T-cell proliferation, T-cell differentiation, suppression of pro-inflammatory cytokines and TCR signalling. Additionally, the metabolic regulation by glycosylation also resulted in a control of disease severity and suppression of the adaptive immune response in vivo, in colitis-induced mouse models.

Conclusion

In this study, we demonstrated how specific glycans could modulate T-cell immune response in IBD.

References

[1] Marth, JD and Grewal, PK. Mammalian glycosylation in immunity. Nat Rev Immunol 2008;8(11):874–87.

[2] Dias AM, Dourado J, Lago P, et al. Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis. Hum Mol Genet 2014;23(9):2416–27.