Figure 1.

Costimulation blockade. Activation of a T cell involves a series of interactive steps with an APC. The first signal imparts antigen specificity and commences when the TCR engages the antigen/MHC complex presented by the APC. This signal is commonly referred to as “signal 1.” In subsequent steps, the T cell receives a number of costimulatory signals, including those following interaction of CD154 on T cells with CD40 on APCs, which matures the APC to upregulate expression of CD80/86. The interaction of CD28 with CD80/86 is termed as “signal 2” and activates APCs to secrete cytokines, which provide the final activation signals to the T cell; this step is commonly referred to as “signal 3.” Protocols based on costimulation blockade can prevent T cell activation by targeting steps in the T cell activation cascade. Anti-CD154 mAb blocks the interaction between CD154 and CD40, and prevents the APC from upregulating CD80/86, blocking full APC activation. This prevents the secretion of proinflammatory cytokines, thus depriving the T cell of signal 3. As a result of costimulation blockade, the T cell does not develop an activated phenotype, and consequently becomes nonresponsive (tolerant) to allogeneic antigens.