Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier

Abstract

Intestinal intraepithelial lymphocytes (IELs) are a large and diverse population of lymphoid cells that reside between the intestinal epithelial cells (IECs) that form the intestinal mucosal barrier. Although IEL biology has traditionally focused on T cells, recent studies have identified several subsets of T cell receptor (TCR)-negative IELs with intriguing properties. New insight into the development, homeostasis, and functions of distinct IEL subsets has recently been provided. Additional studies have revealed intricate interactions between different IEL subsets, reciprocal interactions between IELs and IECs, and communication of IELs with immune cells that reside outside the intestinal epithelium. We review here sentinel functions of IELs in the maintenance of the mucosal barrier integrity, as well as how dysregulated IEL responses can contribute to pathology.

Keywords: intestinal immunity; intestinal inflammation; intraepithelial lymphocytes; lymphocyte development; mucosal immunity.

Figure 1.. Intestinal IEL Classification.

Intestinal IEL can be classified according to their TCR expression profile (i.e., TCRαβ⁺, TCRγδ⁺ or TCR⁻). TCR⁺ IEL can be further subdivided into induced TCR⁺ IEL that are derived from conventional TCRαβ⁺ T cells activated outside of the intestinal epithelium, and natural TCR⁺ IEL that home naturally to the intestinal epithelium following their development. Many induced TCR⁺ IEL become positive for CD8αα expression upon entry into the intestinal epithelium (see arrows). TCR⁻ IEL comprise subsets of cells resembling innate lymphoid cells (ILC), intracellular CD3⁺ (iCD3⁺) cells, and iCD8α cells. Some differences in the prevalence and phenotype of mouse versus human IEL are indicated. Of note, TCRαβ⁺CD8αα⁺ IEL are rare in adult humans, and ILC3-like IELs have not yet been described in mice. It is likely that additional intestinal IEL subsets are yet to be discovered.