The Notch-1 signaling pathway is responsible for homeostatic tight junction expression in vitro, and promotes barrier function in vivo in the RAG1-adoptive transfer model of colitis. In this study, we sought to determine the role of colonic Notch-1 in the lymphoepithelial crosstalk in health and disease. We utilized in vivo and in vitro knockdown to target the expression of Notch-1. We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and upon inflammatory stimulus. Notch-1 expression modulates mucosal chemokine and cytokine secretion, and FoxP3 and effector T-cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium through crosstalk with the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathways that, in turn, elicits T-cell responses. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut. Our findings highlight an indispensable role for Notch-1-mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial proinflammatory responses.

The epithelium of the gastrointestinal tract, which represents the largest surface area of the body, is constantly exposed to the contents of its surrounding environment. The intestinal epithelium forms barriers that are essential in maintaining equilibrium within the human body. This barrier supports nutrient and water transport while preventing microbial invasion. Intestinal epithelial cells (IECs) sit at the interface between an antigen-rich lumen and a lymphocyte-rich lamina propria (LP). IECs have the capability to discriminate between "peaceful" and "harmful" antigens. The epithelium is constantly sampling luminal contents and making molecular adjustments accordingly. These molecular changes influence the actions of innate and adaptive immune cells. The crosstalk that occurs between the epithelium and the immune compartments serves to maintain intestinal homeostasis. A better understanding of the nature of the interactions between normal LP lymphocytes (LPLs) and IECs will ultimately provide insights into the defects occurring in inflammatory bowel disease patients.

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