Grant: Project Grant

Immunity to many infections and the efficacy of vaccination depend on producing sufficient and highly specific antibodies. The quality of the antibodies produced in response to infection or immunization improves with time, by a process that requires that the antibody-producing immune cells, or B-lymphocytes, undergo a complex set of genetic and functional changes. These changes take place in special structures named germinal centers, within lymphoid organs like the spleen or lymph nodes. Inside germinal centers, the B lymphocytes multiply and randomly change the information of the genes encoding the antibody molecules. This generates a repertoire of related B lymphocytes that are triaged according to the quality of the antibody they produce. Those that make the best antibodies survive and transform into another type of cell, which produces large amounts of antibody. This process to confer immunity can be compromised, causing immunodeficiency, or improved to boost vaccination. We have identified an enzyme that is essential for the formation and function of germinal centers and thereby for the antibody response. Preliminary data shows that this enzyme is required to maintain the organization and cellular composition of the germinal centers. We posit that this enzyme regulates the proliferation, movement, and metabolism of B lymphocytes to maintain the complex dynamics of the germinal center. Using mouse models and diverse molecular, biochemical and cellular techniques, we will define the mechanisms whereby this enzyme underpins the antibody response. This project will reveal novel mechanisms regulation the antibody response that can be exploited in the clinic to improve immunity.