The CD28 receptor is stimulated during the contact of T cells with antigenн presenting cells. A counter-receptor for CD28 is the B7 molecule expressed on activated B cells, dendritic cells, and macrophages. B7 also binds to CTLA-4, a receptor that is structurally related to CD28. CTLA-4 is expressed in low copy number by T cells only after activation, but it binds B7 with---20-fold higher affinity than CD28. Inhibition of B7-CD28 interactions blocks immune responses in vitro and in vivo. Therefore, CD28 receptor stimulation is required for T cell responses to antigens and for B cell responses to T-dependent antigens. During T cell responses to antigens, CD28 receptor stimulation may be required to prevent clonal inactivation or anergy. CD28 receptor ligation induces tyrosine phosн phorylation of specific substrates, including phospholipase Cy" and trigн gers both calcium-dependent and calcium-independent signals. The CD28 costimulatory receptor represents a novel target for immunosuppressive drugs.