STRA6-mediated regulation of B-cell immunity

Generation of antibodies that bind to the invading pathogen with high affinity is not only the cornerstone of host resistance to an ongoing infection but also the basis of protective immunity achieved through vaccination. High-affinity antibodies derive from antigen-primed B cells that have undergone rounds of proliferation, genomic mutation of their antigen receptor genes and affinity- based selection within structures called germinal centers. Germinal centers develop following infection or vaccination in the B-cell follicles within secondary lymphoid organs, such as the lymph nodes. Importantly, germinal center formation and their ability to support the generation high-affinity B-cell clones depend on a specialized subset of B-cell follicle-resident fibroblastic stromal cells. Despite the importance of stromal cells in providing the extrinsic milieu that critically supports germinal center function, the mechanisms remain poorly defined. The project is based on an original finding that germinal centers are selectively demarcated by the presence of a receptor controlling cellular intake and availability of vitamin A, STRA6, expressed by stromal cells. We hypothesize that STRA6-mediated regulation of vitamin A homeostasis within germinal centers is a vital mechanism by which stromal cells foster the generation of high-affinity antibodies. We will use a conditional knockout mouse model that enables the selective deletion of STRA6 in lymphoid-organ stromal cells coupled with state-of-the-art cellular, molecular, imaging and omics approaches, to decipher the role of STRA6 in supporting the generation of high-affinity antibodies. The results of the project will enhance our understanding of the functions of both B-cell follicle-resident stroma and vitamin A in the regulation of B-cell immunity, which will be of relevance for translational applications such as vaccinology and the therapeutic use of vitamin A.