Our focus is on understanding the gene regulatory pathways that control cell fate decisions in B cells. During an immune response, resting B cells become activated and are directed to terminally differentiate into a wide variety of final output states that include antibody-secreting plasma cells, memory B cells, and apoptotic cells. We are interested in elucidating the molecular mechanisms by which this differentiation process is regulated within B cells by recently identified homologs of B7 costimulatory ligands and by novel retroviral cDNA library screens designed to functionally identify genes regulating B-cell differentiation.
Identification of a novel costimulatory molecule regulated by NF-kB/Rel transcription factors. In a screen to identify genes induced by NF-kB/Rel transcription factors, we cloned a novel gene, b7h, that is a close homologue of B7 costimulatory ligands expressed on antigen-presenting cells. B7h is expressed on naïve B cells and costimulates proliferation and cytokine production from T cells through the ICOS receptor expressed on activated T cells. Regulation of B7h expression at the level of transcription and protein trafficking on B cells is likely to be a critical set point for controlling B cell-T cell interactions that are necessary for high-affinity antibody production during an immune response. We are exploring how B7h-ICOS interactions regulate antibody production using in vitro assays as well as transgenic and knockout mouse models.
Novel B7 costimulatory ligands. B7h is part of a rapidly emerging family of costimulatory receptor/ligand pairs that regulate immune responses. We are interested in characterizing other family members with a particular emphasis on understanding how the broader expression of these family members regulates effector lymphocyte function at sites of infection.
Functional retroviral screens. Retroviral vectors provide a rapid and effective means to examine the function of different gene products in primary lymphocytes. We are conducting screens with retroviral cDNA libraries to functionally identify genes that control differentiation of primary B cells.