Intraepithelial Lymphocytes: Origins, Distribution, and Function

Intraepithelial lymphocytes (IEL) are associated with the intestinal tract, respiratory tract, genitourinary tract epithelium, and the skin and are the first immune system cells to encounter pathogens that have invaded an epithelial surface. IEL are predominantly T cells (CD3+) with CD8+ cells predominating at most, but not all, sites. Both TCRαβ+ and TCRγδ+ cells are found within IEL populations and an increasing body of evidence suggests that some IEL may arise extrathymically. The presence within intestinal IEL of cells expressing potentially self-reactive TCR suggests that T cell selection within epithelia may differ from thymic T cell selection although recent evidence suggests that these cells may in fact be nonresponsive. IEL exhibit various cytotoxic activities including alloreactive and virus-specific CTL activity, NK activity and spontaneous cytotoxicity, activities consistent with an immune surveillance or first line of defence role. IEL also appear activated in vivo and secrete a variety of cytokines. Subsets of IEL have been shown to provide B cell help, to play a role in the maintenance of oral tolerance and to regulate epithelial cell function. In this review the morphology, distribution and phenotype of IEL, the potential for extrathymic development and possible functions of this unique lymphoid population are discussed.