T cell activation requires two signals: 1) recognition of the antigenic peptide/major histocompatibility complex (MHC) by the T cell receptor (TCR) and 2) antigen-independent co-stimulation induced by interactions between co-signaling molecules expressed on target cells, such as antigen-presenting cells (APCs), and their T cell-expressed receptors. Engagement of the TCR in the absence of this second co-stimulatory signal typically results in T cell anergy or apoptosis. In addition, T cell activation can be negatively regulated by co-inhibitory molecules present on APCs. Therefore, integration of the signals transduced by co-stimulatory and co-inhibitory molecules following TCR engagement directs the outcome and magnitude of a T cell response including the enhancement or suppression of T cell proliferation, differentiation, and/or cytokine secretion. Most co-stimulatory and co-inhibitory molecules belong to either the Immunoglobulin (Ig) superfamily or Tumor Necrosis Factor (TNF) receptor superfamily and are further classified as members of the B7/CD28, butyrophilin, CD2/SLAM, TIM, or nectin- and nectin-like binding receptor subfamilies of the Ig superfamily or as members of the type L or type V subfamilies of the TNF receptor superfamily. Many of these proteins are being investigated as potential targets for cancer immunotherapy as multiple studies have shown that the T cell co-stimulatory/co-inhibitory system can be exploited to improve anti-tumor immunity.
B7 proteins are a family of co-signaling molecules that primarily interact with T cell-expressed immune receptors belonging to the CD28 family (CD28, CTLA-4, PD-1, ICOS, and BTLA). The B7 family consists of ten surface glycoproteins including B7-1/CD80, B7-2/CD86, B7-H1/PD-L1, B7-DC/PD-L2, B7-H2/ICOS L, B7-H3, B7-H4, B7-H5/VISTA, B7-H6, and B7-H7/HHLA2. As shown in the graphic on the next page, interactions between B7 and CD28 family members transduce both T cell co-stimulatory and co-inhibitory signals. Additionally, these interactions can have bidirectional effects (indicated by the two-headed arrows).