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Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation

Abstract

T-cell activation requires clustering of a threshold number of T-cell receptors (TCRs) at the site of antigen presentation, a number that is reduced by CD28 co-receptor recruitment of signalling proteins to TCRs1,2,3,4,5. Here we demonstrate that a deficiency in β1,6 N-acetylglucosaminyltransferase V (Mgat5), an enzyme in the N-glycosylation pathway, lowers T-cell activation thresholds by directly enhancing TCR clustering. Mgat5-deficient mice showed kidney autoimmune disease, enhanced delayed-type hypersensitivity, and increased susceptibility to experimental autoimmune encephalomyelitis. Recruitment of TCRs to agonist-coated beads, TCR signalling, actin microfilament re-organization, and agonist-induced proliferation were all enhanced in Mgat5-/- T cells. Mgat5 initiates GlcNAc β1,6 branching on N-glycans, thereby increasing N-acetyllactosamine6, the ligand for galectins7,8, which are proteins known to modulate T-cell proliferation and apoptosis9,10. Indeed, galectin-3 was associated with the TCR complex at the cell surface, an interaction dependent on Mgat5. Pre-treatment of wild-type T cells with lactose to compete for galectin binding produced a phenocopy of Mgat5-/- TCR clustering. These data indicate that a galectin–glycoprotein lattice strengthened by Mgat5-modified glycans restricts TCR recruitment to the site of antigen presentation. Dysregulation of Mgat5 in humans may increase susceptibility to autoimmune diseases, such as multiple sclerosis.

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Figure 1: Immune phenotype in Mgat5-/- mice.
Figure 2: Mgat5-/- T cells are hypersensitive to TCR agonists.
Figure 3: TCR clustering, actin re-organization and signalling in T cells from Mgat5-/- and Mgat5+/+ mice.
Figure 4: Lactose stimulates TCR aggregation and signalling in Mgat5+/+ mice.

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Acknowledgements

We thank S. Kulkarni and J. Tsang for technical assistance. This research was supported by grants from NCI of Canada, the Mizutani Foundation, the National Science and Engineering Research Council of Canada, and GlycoDesign, Toronto.

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Correspondence to James W. Dennis.

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Demetriou, M., Granovsky, M., Quaggin, S. et al. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409, 733–739 (2001). https://doi.org/10.1038/35055582

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