Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits

LUCIANO MOROSI; CUTINE, ANABELA; ALEJANDRO J. CAGNONI; MANSELLE COCCO, MONTANA; CROCI, DIEGO O.; MORALES, ROSA; MAY, MARÍA; MENDEZ-HUERGO, SANTIAGO; PUCCI, BETINA; GIL, A. H.; HORNOS, S. P.; DOCENA, GUILLERMO H.; SAMBUELLI, ALICIA M.; TOSCANO, MARTA; RABINOVICH, GABRIEL A.; MARIÑO, KARINA V.

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2021

2375-2548

Diverse tolerogenic circuits operate to preserve mucosal homeostasis and to prevent intestinal inflammation. Galectin-1 (Gal1), a β-galactoside-binding protein, promotes immune cell homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent ?on-off? circuit driven by endogenous Gal1 and its glycosylated ligands that controls intestinal immunopathology via selective targeting of activated CD8+ T cells and shaping the local cytokine profile. In inflammatory bowel disease (IBD) patients, augmented Gal1 was associated with dysregulated expression of C2GNT1 and ST6GAL1, critical glycosyltransferases responsible for creating or masking Gal1 ligands. Mice devoid of Gal1 exhibited exacerbated intestinal immunopathology and augmented mucosal CD8+ T-cell activation in response to 2,4,5-trinitrobenzenesulfonic acid (TNBS)-induced colitis; this phenotype was partially ameliorated by treatment with recombinant Gal1. Mice lacking C2GnT1 exhibited aggravated colitis, and, conversely, ST6Gal1-deficient mice showed attenuated inflammation. These effects were associated with the intrinsic glycosylation of mucosal T cells. Thus, specific interactions between endogenous Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating mucosal T-cell immunity.