Molecular and metabolic characterization of gut stromal cells underpinning efficient intestinal B cell response - Abstract The humoral immune response at the intestinal interface has evolved to control commensal communities and prevent entry of pathogenic microbes and toxins. B lymphocytes in the gastrointestinal tract are constantly stimulated by microbial antigens and are geared toward generation of immunoglobulin A (IgA), which is the main antibody isotype found in the intestine. B cells mount a rapid antibody response against bacteria via germinal center reaction, a complex multistep process of B cell proliferation and selection, which leads to the generation of antibody-secreting plasma cells or memory B cells. Central for the germinal center reaction are Follicular Dendritic Cells (FDCs), specialized stromal cells that play a crucial role in displaying antigens to germinal center B cells. While our knowledge of how germinal center B cells develop, survive and function has increased exponentially thanks to the generation of specific genetic model, a detailed, mechanistic map of FDC functions during germinal center reaction in response to intestinal commensals and oral vaccination has not been charted yet, mainly because experimental tools to study FDCs are not available. Several lines of evidence indicate that FDCs play multiple role in organizing B cell response, both via secreted and membrane-bound molecules. In the gut, cells are exposed to multiple environmental cues, so it is conceivable that FDCs might integrate those signals to tune germinal center reaction and IgA response. Yet, the exact mechanistic contribution of FDCs in mounting IgA response remains elusive. In this application, we will generate a novel, inducible Cre mouse to specifically target FDCs. This approach relies on a binary Cre approach therefore increasing specificity. We will test the hypothesis that FDCs are essential for maintenance of IgA titer and continuous humoral response to commensal, toxins and enteric pathogens. We also hypothesize that intracellular and extracellular receptors signaling in FDC is essential to coordinate germinal center reaction and tune proper generation of memory B cells and plasma cells. Our aims are: 1) to develop a FDC inducible split-Cre model, and 2) to dissect metabolic and molecular sensing by FDCs in the intestine. The proposed studies will rigorously examine the role of FDCs on generation and maintenance of intestinal humoral immunity. It is our expectation that these studies will increase our understanding of how intestinal antigen display shapes B cell response and adaptive immunity. Furthermore, these studies will provide a transformative tools for better understanding of the relationship between FDCs and B cell response in the gut across time and states.
