CONTROL OF INTESTINAL INFLAMMATION BY GLYCOSYLATION-DEPENDENT LECTIN-DRIVEN IMMUNOREGULATORY CIRCUITS

LUCIANO MOROSI; ANABELA M. CUTINE; ALEJANDRO J. CAGNONI; MONTANA N. MANSELLE-COCCO; DIEGO O. CROCI; JOAQUÍN P. MERLO; ROSA M. MORALES; MARÍA MAY; JUAN M. PÉREZ-SÁEZ; MARÍA R. GIROTTI; SANTIAGO P. MÉNDEZ-HUERGO,; BETIANA PUCCI; ANÍBAL H. GIL; SERGIO P. HUERNOS; GUILLERMO H. DOCENA; ALICIA M. SAMBUELLI; MARTA TOSCANO; GABRIEL A. RABINOVICH (*) CO-SENIOR; KARINA MARIÑO (*) CO-SENIOR

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2021

2375-2548

Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a beta-galactoside?binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent ?on-off? circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the local cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 beta6-N-acetylglucosaminyltransferase 1 (C2GNT1) and alpha(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,5-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1−/− mice exhibited aggravated colitis, St6gal1−/− mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus,endogenous Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.