Initiation of immune responses requires proper interactions between T cells and antigen presenting cells (APCs). This interaction is thought to be regulated by various cytokines and accessary molecules. Dendritic cells (DCs) serve as potent APCs that lead to the stimulation of native T cells and play a role in the initiation of the immune response. Among various cytokines, the tumor necrosis factor (TNF) family members play an important role in the T-DC dialogue in which DCs respond to the T cell via the TNF receptor (TNFR) superfamily. They have recently coloned a nvel cytokine, termed TRANCE, a type II transmembrane protein, which is a new member of the TNF family. TRANCE expression is restricted to T cells and highly upregulated upon T cell activation. Subsequently, they showed that a high level of TRANCE receptor (TRANCE-R) expression is restricted to mature DCs. Further studies with a recombinant TRANCE protein showed that TRANCE promotes the survival of DCs in vitro. Thus, TRANCE appears to be a survival factor for DCs and is likely to regulate the immune responses by participating in the T-DC interaction. They propose to extend the study of the T-DC interaction controlled by TRANCE/TRANCE-R by pursuing the following specific aims; (1) Generate a panel of monoclonal antibodies against TRANCE and TRANCE-R and determine when and under what circumstances TRANCE and TRANCE-R are expressed, (2) Determine how TRANCE regulates the survival of DCs by studying the signal transduction pathways via TRANCE-R in DCs, (3) Test the potential use of TRANCE to improve the efficacy of DC-based immunization, and (4) Determine the potential role of TRANCE in the immature thymocyte-DC interaction by assessing the role of TRANCE during clonal deletion of self-reactive immature thymocytes. The knowledge gained from studies in this application will provide important insights into the mechanisms of how DC longevity is regulated and how T cells and DCs communicate to regulate each other's functions, which, in turn, may provide a basis for the design of new immunotherapeutic strategies against various tumors or viral diseases which may arise from an inadequate initiation of immunue responses.
|Walsh, Matthew C; Kim, Gregory K; Maurizio, Paul L et al. (2008) TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL. PLoS One 3:e4064|