Activation of T lymphocytes is a requisite event for the induction of antigen specific immune responses against pathogens and tumor cells. T lymphocytes are activated by ligation of a combination of receptors on the surface of a T cell. Although signals from the T cell antigen receptor initiate an activation response, additional signals initiated by engagement of costimulatory receptors regulate the outcome of the T cell activation response. We are interested in characterizing the intracellular signaling events and biological responses that are initiated through the costimulatory receptors CD28 and CD229 (Ly-9) in antigen receptor-activated T cells and thymocytes. We have made CD229 knock out mice and have shown these animals exhibit defective responses to viral infection. We are identifying the cellular mechanisms responsible for these immune response defects to characterize how CD229 regulates immunity. We also are characterizing the intracellular signaling events that are initiated by engagement of CD229 receptors on activated T cells.

A second project involves the characterization of signaling pathways that regulate thymocyte differentiation. We have shown that the drugs that are used to treat HIV infection (HART) affect the thymus by increasing the number of thymocytes that enter the peripheral lymphoid tissues in normal humans. Ongoing studies are focused on characterizing the mechanisms by which HIV protease inhibitors increase thymic output and developing clinical trials to determine if these protease inhibitors will augment the immune systems of cancer patients.

A critical step in thymocyte differentiation occurs when immature double positive (CD4+ CD8+) thymocytes differentiate to single positive (CD4+ CD8- or CD4- CD8+) mature thymocytes. Self reactive thymocytes are eliminated by apoptosis (negative selection) and nonself reactive thymocytes are positively selected to differentiate into mature thymocytes. We have previously demonstrated that CD28 costimulatory receptors interact with T cell antigen receptor signals to stimulate thymocyte apoptosis without stimulating thymocyte maturation. Interestingly, the same costimulatory receptors that regulate apoptosis of thymocytes stimulate the activation, differentiation and anti-apoptotic responses in peripheral T lymphocytes. Biochemical, pharmacologic, and molecular genetic approaches are being used to characterize the signaling pathways that regulate these opposite responses during these important stages in T lymphocyte differentiation.