Building tools to study commensal-specific CD8+ T cells in the small intestine

PROJECT SUMMARY Our understanding of immunity largely stems from models of infection with pathogenic microbes. However, the vast majority of microbial-immune encounters occur as a symbiotic relationship with the commensal microbiota. Recently, the contribution of commensal-specific T cells to host physiology has received significant attention. These commensal-specific responses not only control microbiota containment but also promote microbial diversity within the gastrointestinal tract. Conversely, aberrant immunity to commensal microbes has been proposed to underlie pathologies of barrier tissues, including inflammatory bowel disease. A better understanding of the properties and functions of commensal-specific T cell responses is therefore fundamental to studies of tissue immunity in health and disease. Our long term goal is to better understand how commensal-specific T cell responses contribute to barrier tissue homeostasis, and the objective in this application is to develop novel transgenic mouse models to enable investigation of the mechanisms regulating induction and maintenance of commensal-specific plasma cell responses in the gut. Our rationale for the proposed work is that uncovering these mechanisms has the potential to translate into new therapeutic approaches. Our central hypothesis is that commensal-specific T cells are sentinels of the gut tissue and contribute to intestinal homeostasis by limiting translocation of commensal microbes. In this proposal, we will develop two technically innovative approaches to generate commensal-specific CD8+ T cell receptor transgenic mice, and identify the microbial antigens they recognize. Based on strong preliminary data, we will conduct two specific aims: (1) Develop Segmented Filamentous Bacteria-specific CD8+ T cell receptor transgenic mice and (2) Identify the antigens recognized by Segmented Filamentous Bacteria-specific CD8+ T cells. Our approach is innovative as it investigates new mechanisms of immunity unique to commensal-specific T cell responses. The proposed work is significant because it will establish new insights into the interaction and communication between commensal microbes and immune cells in the gut environment and identify potential targets for therapeutic intervention in conditions of chronic intestinal inflammation.