Signaling via CD28 costimulates lymphokine production, but does not reverse unresponsiveness to interleukin-2 in anti-CD3 triggered Th1 cells

Previously, it has been described that the ability of murine Th1 cells to proliferate in response to exogenous interleukin (IL)-2 is blocked when these cells are exposed to immobilized anti-CD3 antibodies. In the present study we examined whether simultaneous triggering of the T cell antigen CD28 can prevent the induction of unresponsiveness to IL-2 in Th1 cells. We report that costimulation of Th1 cells with anti-CD28 monoclonal antibodies (mAb) did not overcome unresponsiveness to IL-2 induced by various amounts of immobilized anti-CD3 antibodies. However, stimulation with anti-CD28 mAb strongly augmented IL-2 and interferon-γ production in anti-CD3-exposed Th1 cells. Thus, despite the fact that anti-CD28 mAb is a potent costimulus for lymphokine production, signaling through CD28 does not seem to be sufficient to trigger proliferation in Th1 cells activated via the T cell receptor. These data suggest the existence of at least three signals to trigger Th1 cell activation. The first is mediated by ligation of the T cell receptor. One cosignal, delivered by the CD28 molecule, leads to IL-2 production. A third, still undefined, signal is required for proliferation in response to IL-2.