CD28 B7 INTERACTIONS DELIVER A UNIQUE SIGNAL TO NAIVE T-CELLS THAT REGULATES CELL-SURVIVAL BUT NOT EARLY PROLIFERATION/

CD28/B7 ligation provides costimulatory signals important for the deve lopment of T cell responses. In the present study, we examined whether CD28/B7 interactions have a specialized role in the regulation of cel l cycle progression and sustained T cell proliferative responses in na ive T cell populations using TCR transgenic mice. CD28-mediated signal ing was shown to be uniquely capable of regulating cell survival compa red with TCR-mediated signaling. Increasing the strength of the TCR-me diated signal 1 increased early proliferative responses, but had no ef fect on sustained cell survival. In contrast, CD28 ligation, signal 2, was not required for early proliferative responses, but dramatically influenced long term T cell survival. The increased cell survival afte r CD28 ligation was not due to increased IL-2 production, but was link ed to up-regulation of Bcl-x(L). The Bcl-x(L) protein could not be ind uced following increased TCR cross-linking in the absence of CD28 sign aling. In addition, survival of T cells from Bcl-x(L) transgenic mice was not inhibited by blocking CD28 ligation, suggesting that CD28-indu ced T cell survival is regulated by Bcl-x(L) expression. Together, the se results suggest that the unique role of CD28 signaling is not to co stimulate the initial activation of naive T cells, but is, in fact, to sustain the late proliferative response and enhance long term cell su rvival.