T helper lymphocytes are activated in an antigen-specific manner by ligation of the multicomponent T cell antigen receptor. Additional activation signals provided by accessory cell produced IL1 have been shown to be involved in the activation of some T helper lymphocytes. The mechanism by which these IL1 receptor-initiated intracellular responses interact with T receptor-initiated responses to stimulate the T lymphocyte to exit G/0 and transit G/1 phase of the cell cycle remains poorly understood. Although a number of studies have been published about this subject, the data from different T cell model systems are conflicting and no consensus mechanism of action has been identified to explain how the IL1 receptor transmits activation signals into the T cell. Our results have demonstrated that murine T helper lymphocytes can express two IL1 receptor isoforms, which may potentially initiate distinct intracellular signaling events in different cells. The characterization of the functional significance of the IL1 receptor-initiated signals is also complicated by the heterogeneity of the T receptor-initiated responses in different lymphocyte subsets. The direct measurement of intracellular second messenger events in unique T cell model systems has failed to provide a unified paradigm to explain IL1 receptor signal transduction. As an alternative approach, we propose to characterize the Il1-initiated gene regulatory events that are responsible for mediating the competence phase of the T cell activation program. This analysis will identify the IL1- initiated molecular events that are relevant for the activation program and facilitate the identification of second messenger pathways that initiate these events. In addition, we propose to utilize mutagenesis protocols to produce and characterize Il1 receptor signaling deficient mutants. These studies will enable us to identify both signal amplification molecules associated with the IL1 receptors and regions in the IL1 receptor cytoplasmic domain mediating the signal transduction events.
