CD103 engagement regulates intestinal IEL effector function

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PROJECT SUMMARY. Mucosal surveillance of the intestinal barrier by tissue-resident lymphocytes is critical for preventing the invasion of enteric pathogens and a necessary component of protective immunity. A single layer of epithelial cells lines the intestinal tract and provides a physical barrier between microbes, dietary antigens, toxins and the rest of the tissue. Therefore, the reactivation of lymphocytes at the intestinal barrier must be tightly regulated, as too robust of a response could result in destruction of the epithelium leading to microbial translocation and eventual autoimmunity, as observed in inflammatory bowel disease and celiac disease. Tissue-resident intraepithelial lymphocytes (IELs) in the intestine provide a first line of defense against invading microorganisms and the intestinal IEL compartment is composed of what has been termed induced and natural IELs. Induced IELs are CD8ab+ TCRab+ tissue resident memory (Trm IELs) cells that are recruited to the epithelial compartment following antigen exposure. In contrast, natural IELs are not MHC-restricted and include CD8aa+ IELs expressing TCRgd (gd IELs). gd and Trm IELs represent the majority of the lymphocytes in the intestinal epithelium and could serve both protective and pathogenic roles, yet mechanisms regulating their activation during infection in vivo remain largely unexplored. CD103 (aEb7 integrin) is expressed by the majority of gd and Trm IELs located in the intestine and at other barrier sites. CD103 binds to epithelial E-cadherin and plays an important role in the recruitment and maintenance of tissue lymphocytes. However, the contribution of CD103 to IEL functionality within the intestine during infection has not been addressed. Successful completion of the proposed aims will provide fundamental insight into the molecular mechanisms by which CD103 ligation to E-cadherin promotes (1) the motility and activation of Trm and (2) gd IELs and the role of CD103 in promoting protective responses to enteric infection. These studies will uncover novel mechanisms by which direct interaction between IELs and epithelial cells contribute to host immunity and further define the molecular cues regulating sentinel lymphocyte populations in mucosal homeostasis and infection.