Epithelial IL-15 Is a Critical Regulator of γδ Intraepithelial Lymphocyte Motility within the Intestinal Mucosa

Intraepithelial lymphocytes (IELs) expressing the gamma delta TCR (gamma delta IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to gamma delta IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of gamma delta T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for gamma delta IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates gamma delta IEL migration into cultured epithelial monolayers, and inhibition of IL-2R beta significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2R beta signaling induced gamma delta IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of gamma delta T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating gamma delta T cell localization within the intestinal mucosa and regulating gamma delta IEL motility and patrolling behavior as a critical component of host defense.