Fig. 2.

The growing number of B7 superfamily members shaping TCR signaling. CD28 and CTLA-4 have MYPPPY motifs that are essential to bind B7-1 (CD80) and B7-2 (CD86). B7-1 and B7-2 provide important costimulatory signals via an interaction with the constitutively expressed CD28 and provide a negative signal via CTLA-4 (CD152), which is induced upon T-cell activation. ICOS (H4) does not show any binding to B7 and seems to mediate costimulatory effects on recently activated and effector T cells binding to its ligand, ICOS-L (B7 h, B7-H2). B7-H3 is constitutively expressed on IFN-γ–treated DCs and binds to an unidentified receptor on activated, but not on resting, T cells. B7-H3 costimulates proliferation of CD4⁺ and CD8⁺ T cells. PD-L1 (B7-H1) negatively regulates proliferation and cytokine production of T and B cells that express PD-1 upon activation. A secondary receptor mediating costimulatory signals from PD-L1 has been postulated, but not yet identified. This receptor possibly interacts preferentially with PD-L2 (B7-DC). B7x (B7-H4) has been reported to interact with BTLA, which is expressed on activated T and B cells, inhibiting lymphocyte activation. In contrast to the APC shown here, most tumor cells lack B-7 costimulatory molecules and express strongly PD-L1, either constitutively or upon IFN-γ. This expression pattern might shift the costimulatory balance of the TCR signal toward inhibition of tumor-specific T cells when interacting with the tumor cell.