Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes

Abstract

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.

FIGURE 1

Subsets and salient features of iIELs. iIELs include TCR⁺ (red font) and TCR⁻ (blue font) populations, with subsets that are derived from conventional, antigen-experienced T cells (called induced iIELs, red brackets) and subsets that home to the intestinal epithelium immediately after their generation (called natural iIELs, blue brackets). Upon entry into the epithelium induced TCR⁺ iIELs often initiate expression of CD8αα (indicated by blue arrows). The TCR⁻ iIEL population includes subsets resembling ILCs found in barrier tissues outside the intestinal epithelium (i.e., ILC1- and ILC3-like iIELs), cells expressing iCD3 chains (iCD3⁺TCR⁻ iIELs), and cells co-expressing iCD3 and surface CD8αα (iCD8α cells). A few differences between mouse and human iIEL subsets are highlighted. Key features of distinct iIEL subsets, mostly derived from studies with mice, are listed. Localization of iIEL subsets within the figure does not represent their normal distribution among villi and crypts.

FIGURE 2

Development and homeostasis of iIEL subsets. Except for TCRγδ⁺ iIELs, all TCR⁺ (red font) iIEL develop in the thymus. All TCR⁻ (blue font) iIELs develop extrathymically. Induced TCR⁺ iIEL follow a conventional thymic development and selection pathway, whereas natural CD8αα⁺TCRαβ ⁺ iIELs undergo agonist selection. iIELs require a variety of transcription factors for their development and function. Many TCR⁺ iIELs initiate CD8αα expression upon entry into the epithelium. The development, maintenance and homeostasis of iIELs requires a variety of factors, as indicated.