The antigen-presenting cell (APC) plays a key role in the initiation and regulation of immune responses. First, the APC processes and presents antigens in a way that they can be recognized by T lymphocytes. Second, it synthesizes costimulatory molecules that are crucial for the activation of T lymphocytes. Triggering of the T cell receptor in the absence of a costimulatory signal is not sufficient to induce complete T cell activation. In contrast, it can lead to T cell anergy. Furthermore, costimulatory ligands may be involved in selection processes in the thymus. It has been suggested that the B7 antigen functions as the major costimulatory ligand in the activation of interleukin-2 secreting CD4+ T lymphocytes. We have developed reagents that allow us to test this hypothesis and to characterize the precise role of the murine B7 (mB7) molecule in the activation and development of murine CD4+ T lymphocytes. We have expressed the mB7 cDNA in chinese hamster ovary cells and have shown that the resulting cell line is capable of costimulating T cell activation. We have also developed a hamster-anti mB7 monoclonal antibody that is capable of blocking costimulation by mB7. Finally, we are in the process of producing a soluble recombinant form of mB7. Using these reagents we plan in this proposal: (i) to study the expression of mB7 by different APC's and how it is regulated, to study the function of mB7 on different APCs, and to determine which T cell populations respond to mB7 triggering; (ii) to determine whether mB7 plays a role in the prevention/maintenance of T cell anergy and whether it is required for immune responses in vivo; (iii) to analyze whether mB7 plays a role in thymic development. We anticipate that our studies will provide important insights into the biology of the immune system. Furthermore, studies on the biologic role of mB7 may provide the basis for further clinical investigations. A pharmacological reagent that interferes with triggering of the costimulatory pathway, e.g. an altered ligand (B7), has the potential to induce T cell tolerance and may be useful in the prevention of allograft rejection. It is also conceivable that a recombinant form of B7 may be useful in situations where it is desirable to upregulate immune functions, for example in the generation of vaccines.
