MOLECUALR BASIS OF T-CELL HELPER FUNCTION

The overall goal of the proposed research is to further understand the mechanisms by which CD4+ T cells promote B cell activation and differentiation into immunoglobulin secreting cells in a process termed, help. Activated CD4+ T cells express cell surface molecules that are critical in delivering contact dependent helper signals to B cells. The activation induced CD4+ T cell surface structures that mediate this function have been, until recently, unknown. Central to this grant is the recent identification of a novel cell surface molecule, termed T-BAM, that is exclusively expressed on activated CD4+ T cells and not on CD8+ T cells. An antibody to T-BAM, mAb 5C8, inhibits T dependent B cell activation and differentiation in vitro. Furthermore, mAb 5C8 identifies T-BAM expressing CD4+ T cell in vivo exclusively within secondary lymphoid tissue, and particularly localized in the mantle and centrocytic zones of germinal centers. These studies suggest that T-BAM is an important CD4+ T cell surface molecule that delivers contact signals to B cells required for B cell activation and differentiation. Based on these findings we propose to further study the role of T-BAM in mediating discrete aspects of CD4+ T cell effector functions. Therefore, we plan to clone and sequence the cDNA encoding T-BAM and study the function of T-BAM when expressed on novel cellular backgrounds. In addition, we will attempt to identify the B cell counter-receptor for T-BAM. Together, these studies will lead to a better understanding of the process by which CD4+ T cells regulate the humoral immune response and may lead to insights regarding the immunopathogenesis of diseases characterized by hypo- or hypergammaglobulinemia.