UC-associated autoantibodies to αvβ6 inhibit mucosal TGFβ activation and predispose to intestinal inflammation.

Ulcerative colitis (UC) is characterized by epithelial barrier dysfunction and dysregulated mucosal immune responses; however, the mechanisms driving disease onset remain poorly defined. Autoantibodies against the epithelial-restricted integrin αvβ6 are a highly specific biomarker of UC that can precede clinical diagnosis by up to 10 years. Because αvβ6 activates TGFβ at epithelial surfaces, we hypothesized that UC-associated αvβ6 autoantibodies inhibit mucosal TGFβ activation and disrupt epithelial homeostasis. We showed that αvβ6 autoantibodies were enriched in UC and that IgG from autoantibody-positive individuals inhibited αvβ6-dependent activation of TGFβ. αvβ6 blockade dampened TGFβ signaling and altered differentiation-associated gene programs in human intestinal epithelial cells. In mice, deletion of αv caused expansion of inflammation-associated goblet cells in the colon and changes in intestinal immune cells. Using a novel mouse model, we showed that αvβ6-specific autoantibody disrupted epithelial-immune crosstalk and increased susceptibility to DSS colitis. Together, these findings establish anti-αvβ6 autoantibodies as active inhibitors of epithelial TGFβ signaling, constituting a de facto anti-cytokine response, rather than passive biomarkers. By linking preclinical seropositivity to impaired epithelial signaling and heightened susceptibility to colitis, this work identifies epithelial αvβ6-dependent TGFβ activation as a pathway that may be leveraged to modify disease risk or limit disease severity.