부산대학교 도서관

Summary: CD40 is a receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on B lymphocytes and other antigen-presenting cells of the immune system. Signals downstream of this receptor play essential roles in multiple aspects of T cell-dependent B cell-mediated humoral immune responses. These functions include the clonal expansion of antigen-specific B cells, organization and maintenance of germinal centers, immunoglobulin isotype switching and memory B cell formation. Biochemically, CD40 is known to activate multiple intracellular signaling pathways, including the nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38 kinase and phosphatidylinositol-3 kinase (PI-3K) pathways; however, the extent of overlap between these pathways, both in activation and in their contribution to CD40 responses, are unclear. In the present work, we provide evidence that the divergence of the NF-κB and JNK pathways occurs at the level of TNFR-associated factor (TRAF) adaptor molecules through structure-function analyses and through the characterization of a novel TRAF-interacting protein that cooperates with a member of the TRAF family to promote the specific activation of the JNK pathway. To determine if this divergence is reflected in downstream responses, we examine the individual contributions of multiple CD40-activated pathways to global gene expression responses. As a model system linking gene expression to biological function, we demonstrate an essential role of the NF-κB pathway in B cell survival through the induction of the anti-apoptotic molecules Bcl-x and Bfl-1. Thus we develop a global model for the contributions of multiple signaling pathways to subsets of an overall response to CD40 stimulation.