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

Michael Demetriou, Maria Granovsky, Sue Quaggin and James W. Dennis ()
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Michael Demetriou: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Maria Granovsky: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Sue Quaggin: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
James W. Dennis: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Nature, 2001, vol. 409, issue 6821, 733-739

Abstract: 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.

Date: 2001
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DOI: 10.1038/35055582

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