Figure 1.

Interactions between co-stimulatory and co-inhibitory B7 and CD28 family members. B7 family ligands belong to the immunoglobulin superfamily and contain immunoglobulin-V-like and immunoglobulin-C-like domains. B7-1 and B7-2 are expressed on APCs, and function primarily to regulate the initial T cell priming by engaging CD28 or CTLA-4 receptors found on naïve and activated T cells, respectively. The expression of other B7 ligands is not limited to APCs, and is also found in non-lymphoid organs. ICOSL, PD-L1, PD-L2, B7-H3 and B7-H4 signaling mediate peripheral tolerance, and their expression in cancer have been predictive of patient prognosis. CD28 family receptors are also part of the immunoglobulin superfamily, but consist of a lone immunoglobulin-V-like domain. CD28 and CTLA-4 compete for B7-1 and B7-2 during early stages of T cell response, whereas the engagement of ICOS to ICOSL, and of PD-1 to PD-L1/PD-L2 mediate the function of pre-activated T cells. To date, the receptors for B7-H3 and B7-H4 remain unidentified, although several candidates have been proposed. In addition to the canonical B7:CD28 signaling pathways, B7-1 has also been demonstrated to reverse signal upon PD-L1 engagement, adding to the complexity of how B7-mediated signals function during tumor growth. Receptors with established T cell co-stimulatory functions are in red; those with co-inhibitory roles in blue.