The costimulatory pathway involving B7 costimulatory molecules and their receptors CD28 and CTLA-4 is of major importance. Our studies have revealed striking and unexpected functions of costimulatory pathways. Our studies revealed that B7-2 is the major early activating costimulator in this pathway. These mice develop splenomegaly and lymphadenopathy, multiorgan lymphocytic infiltration, and tissue destruction and die by three to four weeks of age. This critical negative immunoregulatory function of CTLA-4 provides a previously unsuspected means by which costimulation can regulate responses to self antigens and potentially offers new approaches for manipulating activated T cells.
Current research focuses in three areas.
The laboratory is defining mechanisms by which B7 costimulators play a critical role in T cell activation. Secondly, we are analyzing the critical negative regulatory role of CTLA-4 in T cell activation and tolerance. Analysis of immune response of B7 deficient strains to model protein antigens, viruses, and parasites. Analysis of role of CTLA-4 in T cell tolerance and autoimmunity. Analysis of the function of B7h and B7h-1 costimulatory molecules.