Grant: Operating Grant

Antibodies are important proteins in the defense from disease causing pathogens. Memory B cells and plasma cells are the two principal cell populations that establish and maintain antibody levels. This is significant in light of the fact that most, if not all successful vaccines induce antibodies that neutralize the invading pathogen. Consequently, it is of critical importance to identify the mechanisms that regulate the activation of memory B cells. We identified a family of proteins termed Fc Receptor-Like (FCRL) that is predominantly expressed on memory B cells. These proteins have a strong regulatory potential on the activation of B cells. Of interest, the FCRL4 family member is expressed only by a subpopulation of human memory B cells that is impaired in the infectious diseases HIV and malaria and encodes the majority of the antibodies that are specific for HIV. The FCRL proteins represent a level of regulation of memory B cells that so far is not understood. Specifically, FCRL4 subjects a defined subpopulation of memory B cells to an additional level of regulation, the reason of which is unknown. In this research proposal we address several aspects of FCRL-mediated regulation of memory B cells. Key to the understanding of FCRL molecules is the elucidation of the mechanism by which FCRL4 regulates the activation of memory B cells. In a second approach we will examine the characteristics of the antibodies that are produced by FCRL4-bearing memory B cells. In a third approach we will investigate the origins and developmental fate of FCRL4-bearing memory B cells. The results from these studies will give us a better understanding of the mechanisms that regulate human memory B cells. This in turn will aid in the development of new vaccine designs to diseases to which current vaccination strategies are not successful and will help to understand how failure of proper FCRL-mediated regulation contributes to B cell disorders.