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, 34 (11), 556-63

B7 Family Checkpoint Regulators in Immune Regulation and Disease


B7 Family Checkpoint Regulators in Immune Regulation and Disease

Sabrina Ceeraz et al. Trends Immunol.


Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target.

Keywords: B7 family; co-inhibitory molecules; co-stimulatory molecules.


Figure 1
Figure 1. B7 Family of co-stimulatory and novel co-inhibitory molecules
T cell activation requires two signals. Signal 1 is mediated by Major histocompatibility complex (MHC) molecules presenting cognate peptide (P) on antigen presenting cells (APCs) to the T cell receptor (TCR) on T cells forming an MHC-P complex. To sustain full T cell activation, a second signal is required to deliver either a co-stimulatory (B7-H1/B7-H2-CD28, inducible costimulator (ICOS) - inducible costimulator ligand (ICOSL) or co-inhibitory (B7-H1/B7-H2-cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death ligand -1/2 (PD-L1/PD-L2) - programmed cell death 1 (PD-1), B and T lymphocyte attenuator (BTLA) - herpesvirus entry mediator (HVEM) signal. The receptors for B7-H3 and B7-H4 are unknown. Studies indicative that B7-H3 binds to putative co-stimulatory and co-inhibitory receptors. In contrast, B7-H4 binds to a putative co-inhibitory receptor only. The receptor for the inhibitory ligand V-domain Ig suppressor of T cell activation (VISTA) is unknown. Functional studies show that VISTA delivers a negative signal to the T cell.

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