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

Michael Demetriou, Maria Granovsky, Sue Quaggin, James W. Dennis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

685 Scopus citations

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 TCRs 1-5. 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-acetyllactosamine 6, the ligand for galectins 7,8, which are proteins known to modulate T-cell proliferation and apoptosis 9,10. 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.

Original languageEnglish (US)
Pages (from-to)733-739
Number of pages7
JournalNature
Volume409
Issue number6821
DOIs
StatePublished - Feb 8 2001

ASJC Scopus subject areas

  • General

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