Signal Transduction Via Co-stimulatory and Co-inhibitory Receptors

T-cell receptor (TCR)-mediated antigen-specific stimulation is essential for initiating T-cell activation. However, signaling through the TCR alone is not sufficient for inducing an effective response. In addition to TCR-mediated signaling, signaling through antigen-independent co-stimulatory or co-inhibitory receptors is critically important not only for the full activation and functional differentiation of T cells but also for the termination and suppression of T-cell responses. Many studies have investigated the signaling pathways underlying the function of each molecular component. Co-stimulatory and co-inhibitory receptors have no kinase activity, but their cytoplasmic region contains unique functional motifs and potential phosphorylation sites. Engagement of co-stimulatory receptors leads to recruitment of specific binding partners, such as adaptor molecules, kinases, and phosphatases, via recognition of a specific motif. Consequently, each co-stimulatory receptor transduces a unique pattern of signaling pathways. This review focuses on our current understanding of the intracellular signaling pathways provided by co-stimulatory and co-inhibitory molecules, including B7:CD28 family members, immunoglobulin, and members of the tumor necrosis factor receptor superfamily.