UNIVERSITY OF MASSACHUSETTS
T cells are involved in many beneficial aspects of the immune system including the control of infections, tumor surveillance, generation of B cell responses, and regulation of homeostasis. In some instances, activated T cells are also detrimental to a host, mediating autoimmune disease, allergic reactions, immunopathology, and the rejection of transplanted tissues. The activation of na?ve T cells is a tightly controlled process, involving a complex network of signaling events that is still not completely understood. The early stages of T cell activation are critical to the programming of differentiation pathways for T cells, and this process is extremely sensitive to levels of inflammation. We have shown that na?ve phenotype T cells rapidly produce TNF within 5 hours of TCR engagement. This result was unexpected because naive T cells are thought to acquire effector functions only after undergoing a differentiation process and suggests that na?ve T cells produce this inflammatory cytokine during the innate phase of the immune response. Our recent data indicate that T cell-produced TNF has a suppressive effect on the generation of anti-viral responses, as TNF-deficient virus-specific T cells are present at significantly higher frequencies after infection as compared to wild type T cells. These findings reveal a novel self-regulatory function for antigen-specific T cells that is mediated by the production of TNF. The long-term goals for this proposed research plan are to further characterize the role of T cell-produced TNF in the generation of T cell responses and to determine if antagonizing TNF-activity at early times after infection will enhance immune responses. The specific hypothesis to be tested is that T cell-produced TNF has important regulatory functions for the development of functional cellular immunity. We propose to evaluate the importance of T cell-produced TNF by the following specific aims: SPECIFIC AIM#1: To determine the mechanisms by which T cell-produced TNF regulates the generation of virus-specific T cell responses. SPECIFIC AIM#2: To determine if a transient blockade of TNF-signaling will enhance the generation of virus-specific T cell responses after infection and vaccination.