CD8αα TCRαβ Intraepithelial Lymphocytes in the Mouse Gut

The epithelium of the mouse small intestine harbors an abundant CD8αα⁺TCRαβ⁺ intraepithelial lymphocyte (IEL) population. This unique IEL subset is a self-reactive population that requires exposure to self-agonists for selection in the thymus, similarly to other regulatory T cell populations. After leaving the thymus, these cells directly seed the intestinal epithelium, which provides a unique combination of cellular interactions together with cytokines, nutrients, and antigens that guide the lineage-specific differentiation and function of these IELs. For instance, epithelial cells and nearby immune cells secrete a number of cytokines, including interleukin-15 (IL-15), IL-7, and transforming growth factor-β, resulting in an assortment of cellular responses, including activation of master transcription factors, cell proliferation, and cytokine secretion. Recent advances have also highlighted the importance of diet-derived substances and commensal metabolites, such as the aryl hydrocarbon receptor ligands and vitamin D, in controlling the survival and gene expression of CD8αα⁺TCRαβ⁺ IELs. Furthermore, these cells function in the epithelium and require constant communication between cells in the form of cell-to-cell contacts. These interactions tune the antigen sensitivity of the TCR and maintain the quiescence of the CD8αα⁺TCRαβ⁺ IELs. Finally, we discuss how these cells might contribute to tolerance and immunopathological responses in the gut. Therefore, an increased understanding of CD8αα⁺TCRαβ⁺ IELs in the gut will help us understand how these cells participate in immune regulation and protection.