Localization of TCR-expressing natural intraepithelial lymphocytes in the colon epithelium depends on GPR15 and epithelium-derived C10ORF99

Intraepithelial lymphocytes (IELs) are among the largest lymphocyte populations in the body and play a crucial role in maintaining the integrity of epithelial barriers at mucosal sites, which are highly immunostimulatory. Therefore, understanding how these cells are generated, localized within the epithelium, and contribute to barrier immunity is essential. Although most research on IEL biology has focused on the small intestine, IELs are also present in the large intestinal epithelium. Additionally, the homing receptor-ligand pairs that regulate T cell localization in the lamina propria beneath the epithelium differ between the small and large intestines: CCL25-CCR9 in the small intestine and C10ORF99-GPR15 in the large intestine. CCL25-CCR9 is also necessary for proper localization of IELs in the small intestine, but the mechanisms controlling IEL localization in the large intestine remain unknown. Here, we demonstrate that the C10ORF99-GPR15 pathway is crucial for the presence of TCR + natural IELs in the large intestinal epithelium, a process that requires epithelium-derived C10ORF99 (GPR15L).