Background & Aims: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1Bmediated protein sorting in the maintenance of gastrointestinal immune homeostasis. Methods: The role of AP-1B in intestinal immunity was examined in AP-1Bdeficient mice (Ap1m2-/-) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1Bmediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2-/- mice. Results: Ap1m2-/- mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17Aproducing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. Conclusions: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1Bmediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.
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