Physiologically relevant full activation of T cells requires signal transduction through the T cell receptor and additional costimulatory cell surface molecules. Best understood of these costimulatory interactions are those between CD28 and its ligands B7-1 (CD80) and B7-2 (CD86). While B7-1 and B7-2 bind the same receptors (CD28 and CTLA-4), they share only 25% sequence homology, are expressed at different times during immune responses, and in some systems have been shown to differentially affect T cell cytokine expression. Although CD28 is an activation antigen, its expression is down-regulated after engagement by B7-1. Here we show that B7-2 engagement is considerably less effective at down-regulating CD28, which indicates a differential effect of these two CD28 ligands on activated T cells.