The effects of B7-dependent costimulation on T cell division and survival in vivo and in vitro are dependent on antigen concentration

We used 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester labeled TCR-transgenic CD4+ T cells to investigate the contribution of B7 costimulation to T cell activationand clonal expansion. B7 costimulation was blocked with the fusion protein cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Ig, which prevents the interaction of B7 with its receptor CD28 on T cells. CTLA4-Ig had different effects depending on the density of antigen (Ag)/MHC ligands available by T cells. In the presence of CTLA4-Ig, tenfold higher concentrations of Ag were required for T cells to undergo cell division in vitro. At high Ag concentrations, T cell division occurred at comparable rates whether in the presence or absence of CTLA4-Ig; however, T cell survival and clonal expansion were strongly inhibited. Addition of IL-2 restored T cell survival but not responsiveness to low doses of Ag. In vivo, B7 costimulation was similarly required for the survival of Ag-specific T cells but not for cell division in response to high amounts of Ag. Thus, B7 costimulation regulates CD4+ T cell responses by promoting cell division in the presence of limiting amounts of Ag, and by protecting T cells from the onset of apoptosis.