Costimulation is a pivotal process in T cell activation. Engagement of the appropriate MHC-peptide complex with TCR in the absence of a costimulatory signal 'will lead to anergy. The B7-CD28 costimulatory pathway is extremely significant since a blockade of this pathway results in dramatic effects on T cell dependent immune responses in vitro and in vivo. This phenomenon provides the opportunity to understand the immunologic foundation of certain disease processes as well as to plan therapeutic intervention strategies. The B7-CD28 pathway is comprised of two ligands on APC's, B7-1 and 2, and two receptors on T cells, CD28 and CTLA4. Much of our knowledge regarding the in vivo role of these molecules have stemmed from blocking studies using specific monoclonal antibodies or a soluble receptor fusion protein, CTLA4-Ig. We have shown that alternate B7 transcripts as well a potential B7 isoforms represent an additional dimension to the regulation of this costimulatory pathway. Additionally, we have generated B7- 1 and B7-2 deficient mouse strains to systematically and unambiguously dissect the role of each ligand in the development and function of the immune system. These mouse strains have already proven seminal in demonstrating that the function of the ligands, B7-1 and B7-2 are distinct and not identical.
The specific aims of this proposal are intended to expand and further these initial findings. Specifically we plan: 1) To continue to characterize alternate transcripts from the B7 locus and study their modulation. 2) To characterize potential costimulatory activity of B7 protein isoforms and 3) To further our understanding of the role of B7 costimulation in immune function by extending our studies on model protein antigens to viral models of infection.
