ST8Sia6-dependent glycosylation restrains gut inflammation and pathogenic Th1 and Th17 programs.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract. Pathogenesis of IBD is multifactorial and incompletely understood. Here, we show that the sialyltransferase ST8Sia6 regulates gut inflammation and homeostasis. ST8Sia6-deficient mice spontaneously accumulate activated immune cells in the small intestine and exhibit enhanced sensitivity to dextran sodium sulfate-induced colitis. ST8Sia6-knockout small bowel lamina propria T cells exhibit steady-state increases in Th1 and pathogenic Th17 programs and readily generate TNF-α upon in vitro stimulation. In addition, there are increased levels of inflammation-induced chemokines CCL3, CCL4, and CCL5 in ST8Sia6-deficient immune and epithelial cells. ST8Sia6-deficient T cells show altered glycosylation of CD43 and CD45. ST8Sia6 heterozygous mice show an intermediate phenotype, demonstrating that gut immune homeostasis is sensitive to ST8Sia6 expression levels. This work thus establishes a role for immune cell glycosylation by ST8Sia6 in IBD.