Figure 2. Costimulatory signaling network.
Integration of both positive and negative costimulatory signals during and after initial T cell activation will determine the fate and intensity of the alloimmune response. The complexity of the costimulatory network is exemplified by the potential effects of B7-1 targeting (such as accomplished by CTLA-4-Ig) – while blockade of B7-1 decreases positive costimulatory signaling through CD28 (A), it may affect two inhibitory signaling pathways, preventing B7-1 engagement of CTLA-4 (B) and PD-L1 (C). Dashed line represent the still controversial issue of reverse signaling through PD-L1 or PD-L2.