Mechanisms of gamma delta intraepithelial lymphocyte regulation of intestinal innate immunity



 DESCRIPTION (provided by applicant): γδ IELs are located within the intestinal epithelial monolayer, and the close proximity of these cells to the intestinal lumen positions γδ IELs to ac as immediate responders to enteric pathogens. In the absence of γδIELs, translocation of both commensal bacteria and enteric pathogens is enhanced, demonstrating the unique ability of γδ IELs to bridge innate and adaptive immunity. This innate immune function is demonstrated by the crosstalk that occurs between intestinal epithelial cells and γδ IELs to promote the release f anti-microbial factors in response to Salmonella infection. I have reported that γδ IEL migration provides continuous surveillance of the villous epithelium in an occludin-dependent manner and that this motility is sufficient to limit S. typhimurium translocation; however, the role of γδ IL migration and subsequent epithelial interactions in the activation of innate immunity remains unknown. During my K01 studies, I developed the tools necessary to assess and genetically modulate γδ IEL/epithelial interactions in response to an enteric pathogen. Building on these novel approaches, the proposed R03 studies will begin to identify the cellular mechanism(s) by which γδ IELs and their interactions with epithelial cells promote an immediate innate immune response to prevent bacterial translocation. My central hypothesis is that γδIEL migration and subsequent epithelial interactions are necessary for the immediate production of soluble mediators involved in innate immunity. To test this hypothesis, I will first determine the requirement for occludin-dependent γδ IEL migration on γδ IEL and epithelial cell production of soluble immune mediators and then assess the cellular mechanisms by which these soluble factors contribute to γδIEL-mediated protection against bacterial invasion. These studies will provide new mechanistic insights into the functional role of γδ IELs as the first line of defense against luminal pathogens. The results are expected to serve as the foundation for future study of how γδ IELs mediate an innate immune response to commensal bacteria or in the context of defective host pathogen recognition responses in intestinal diseases such as IBD. This may lead to new strategies to assess γδ IEL/epithelial interactions and function within the intestina mucosa as means to treat disease.