γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice

BACKGROUND & AIMS: Intraepithelial lymphocytes that express the gamma delta T-cell receptor (gamma delta IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether gamma delta IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection. METHODS: Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor delta chain (Tcrd) or CD103, or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of green fluorescent protein (GFP)-tagged gamma delta T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of gamma delta IEL migration on early pathogen invasion and chronic systemic infection. RESULTS: Morphometric analyses of intravital video microscopy data showed that gamma delta IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hour, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO gamma delta T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient gamma delta T cells, whereas invasion in CD103 KO mice, which have increased migration of gamma delta T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of gamma delta T-cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient gamma delta IELs, relative to those with wild-type or CD103 KO gamma delta IELs. CONCLUSIONS: In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to gamma delta IEL surveillance and immediate host defense. gamma delta IEL occludin is required for early surveillance that limits systemic disease.