Dr. Sharpe's research is focused on understanding the role of costimulatory molecules in T cell activation in vivo. Learning how to manipulate costimulatory pathways may provide new therapeutic approaches for augmenting immunity to microbes and tumor antigens, as well as for inhibiting immune responses to prevent graft rejection and treat autoimmune diseases. The approach that her laboratory has taken is to focus on the obligatory in vivo functions of costimulatory molecules by using targeted gene disruption to generate mouse strains lacking T cell costimulatory molecules. Analysis of the key costimulatory pathway involving B7 costimulatory molecules and their receptors, CD28 and CTLA-4, has been her major focus. Her laboratory is investigating the role of B7-1 and B7-2 in T cell activation, T cell tolerance, and autoimmune responses. By examining what factors elicit residual immune responses in mice lacking both B7 costimulators, her laboratory is also examining the role of additional costimulatory pathways in T cell activation. The laboratory is studying interactions between costimulatory pathways and the hierarchy of costimulatory pathways throughout the generation and analysis of mice lacking other costimulatory molecules (including CD48, OX40 ligand, CD40 ligand and SLAM). A second project focuses on analyzing the critical negative regulatory role of CTLA-4 in T cell activation and tolerance. The third project is directed at defining the molecular basis for the highly regulated expression of B7 costimulatory molecules. Because genetic mapping studies have identified the chromosomal regions containing CD28/CTLA-4 and B7/B7-2 loci as important for the development of IDDM and EAE, the laboratory is also examining whether polymorphisms within these genes lead to altered expression or protein function in autoimmune prone mouse strains, thereby contributing the pathogenesis of autoimmunity.