Molecular determinants of intraepithelial lymphocyte function in intestinal infection (360G-Wellcome-206246_Z_17_Z)

Intraepithelial lymphocytes (IEL) are the first immune cells that pathogens encounter in the gut. These lymphocytes lie within the epithelial layer, and are central to controlling infection, stress or transformation of the gut epithelium. Despite their importance, we have a poor understanding of how IEL sense and respond to stress in epithelia, partly due to the lack of genetic tools that specifically target IEL. To get unbiased insights into the complex biological processes underlying IEL function, I determined the quantitative proteomes of three main intestinal IEL subsets. This unique dataset reveals that IEL are phenotypically and functionally distinct from conventional T cells. The IEL proteomes provide unprecedented insights into the effector functions of intestinal IEL and suggest new hypotheses of how their function might be regulated. Based on these data, I will (1) explore the apoptotic and non-apoptotic functions of abundantly expressed granzymes in IEL, (2) develop novel genetic tools to dissect the role of IEL in the early immune response to pathogens, and (3) address the contributions of inhibitory receptors and their signalling pathways to IEL homeostasis and sensing of epithelial dysbiosis. In summary, the proposed research will reveal how IEL communicate and respond to bacterial and parasitic infections.