The physiological activation of and specificity of the T cell response is conferred by the polymorphic antigen-specific T cell receptor (TcR) interacting with cells bearing antigen in association with products of the MHC. TcR-CD3 engagement (""""""""signal 1""""""""), however, is necessary but not sufficient for T cell activation. A second """"""""costimulatory"""""""" signal (""""""""signal 2""""""""), qualitatively different from the signal transduced via the TcR-CD3 complex, is necessary for antigen-specific T cell activation. In the absence of costimulation, TcR-CD3 signaling may result in functional unresponsiveness, or anergy, in mature T cells. The glycoprotein B7/BB1, expressed on the surface of antigen-presenting cells (APC), is a potent costimulator molecule. B7/BB1 binds to both CD28 and CTLA-4 on the surface of T lymphocytes. The CD28/CTLA-4:B7 interaction has been shown to be critical for IL-2 production; in its absence, TcR engagement results in antigen-specific tolerance or anergy. Relatively little is known, however, about the molecular mechanisms by which the CD28/CTLA-4:B7 interaction regulates TcR signaling and costimulation, nor about the differential biochemical signal pathways recruited in T cell stimulation versus tolerance. The primary goal of this project is to identify the intercellular mechanisms involved in costimulation and in tolerance. Towards this goal, we will investigate the biochemical signal transmission pathways important for each of these functions. We will employ a number of approaches to identify cytoplasmic effector molecules that interact directly or indirectly with CD28 during signaling events (Specific Aim 1) and, later, as a result of a tolerizing signal (Specific Aim 3). Second, we will examine the mechanisms by which the B7:CD28 interaction causes an increase in IL-2 mRNA synthesis and protein (Specific Aim 2). At least part of the increase in IL-2 mRNA levels is known to be due to transcriptional activation and will identify the nuclear factors binding to these elements. Lastly, we will determine whether we can inhibit the induction of tolerance or reverse anergy by manipulating the biochemical signaling pathways characterized in Specific Aim 1 and 2.
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