The intestine is continuously exposed to commensal microorganisms, food, and environmental agents and also serves as a major portal of entry for many pathogens. A critical defense mechanism against microbial invasion in the intestine is the single layer of epithelial cells that separates the gut lumen from the underlying tissues. The barrier function of the intestinal epithelium is supported by cells and soluble factors of the intestinal immune system. Chief among them are intestinal intraepithelial lymphocytes (iIELs), which are embedded in the intestinal epithelium and represent one of the single largest populations of lymphocytes in the body. Compared with lymphocytes in other parts of the body, iIELs exhibit unique phenotypic, developmental, and functional properties that reflect their key roles in maintaining the intestinal epithelial barrier. In this article, we review the biology of iIELs in supporting normal health and how their dysregulation can contribute to disease.
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