The goal of this proposal is to identify and characterize novel costimulatory pathways of T cells that play a role in inflammatory lung disease. Under most circumstances TCR-mediated signal transduction alone is not sufficient to fully activate a T cell. After engagement of their TCR by antigen presented in the context of MHC molecules on antigen- presenting cells (APC), lymphocytes must make further decisions to proliferate and acquire effector functions, be rendered anergic, or die by programmed cell death (PCD). Rapid expansion of antigen-specific lymphocytes allows effective eradication of invading pathogens. Therefore, PCD of lymphocytes is a necessity at the end of an immune response, to maintain homeostasis of the immune system and to eliminate potentially auto-reactive cells that could harm the host. The final fate of T lymphocytes is determined by accessory or co-stimulatory signals received either during TCR engagement or shortly thereafter. Several members of the TNF (tumor necrosis factor) receptor family including CD30 have been identified as potential costimulatory receptors on T cells. In vitro and in vivo data indicate a role of CD30 in The cells. The-mediated effects are thought to play a pivotal role in asthma. Therefore, we hypothesize that CD30 plays a role in triggering allergen- induced pulmonary inflammation. Upon engagement by its ligand, CD30 can recruit members of an intracellular adapter protein family, the TNFR-associated factors (TRAF), to their cytoplasmic domains. This event is the initial step of formation of multi-protein complexes that regulate activation and differentiation as well as survival of cells. One important mechanism by which costimulation amplifies an immune response is through enhancement of lymphocyte survival. By studying molecular mechanisms triggered by CD30 and comparing these pathways to those engaged by other costimulatory receptors including CD28 and OX40, we will further define mechanisms that regulate lymphocyte survival during a peripheral immune response. Characterization of factors involved in pathways that regulate lymphocyte survival following antigen encounter will be used for development of strategies to modulate peripheral T cell tolerance and to interfere with auto-immune disease and asthma.
