The B7:CD28 family and friends: Unraveling coinhibitory interactions

Abstract

Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights.

Figure 1.. Costimulatory and coinhibitory receptor-ligand interactions in the B7-CD28 family

The TCR is activated by recognition of peptide antigen presented by MHC and this gives specificity to the T cell response. Optimal T cell activation requires a second, costimulatory signal. B7-1 or B7-2 on APC bind to CD28 on T cells and provide a costimulatory signal. T cell activation is modulated by further stimulatory or inhibitory pathways between APC and T cells. These pathways regulate the fate of T cells, their differentiation into effector, memory, and regulatory T cells and their function. Some of the receptors/ligands are expressed on both APC and T cells as described in Table 1 and the text. Tumor cells and other cells can also express some of these receptors/ligands as described in Table 1 and the text.

Figure 2.. Novel interactions among B7-1, PD-L1, CD28, CTLA-4, and PD-1

B7-1 can form a back-to-back homodimer (interaction surface denoted as dark green on B7-1 IgV domain). A single B7-1 can interact with CD28 to deliver a co-stimulatory signal for T cell activation (interaction surface denoted as orange on B7-1 IgV domain). The B7-1 homodimer can interact with CTLA-4 in a multimeric fashion and CTLA-4 can remove and internalize the B7-1 by trogocytosis (interaction surface denoted as orange on B7-1 IgV domain), resulting in loss of B7-1 costimulatory activity. PD-L1 can interact with PD-1 (interaction surface denoted as light green on PD-L1 IgV domain), leading to phosphorylation of the PD-1 ITIM and ITSM tyrosines, recruitment and activation of SHP-2, and inhibition of T cell activation. B7-1 can interact with PD-L1 to form a heterodimer in which the B7-1 can still engage CD28 or CTLA-4 but the PD-L1 cannot engage PD-1. The CD28 signal remains active but the PD-1 signal is diminished. The CTLA-4 interaction is unimolecular since the B7-1 is monomeric but the CTLA-4 can still trogocytose the B7-1, resulting in loss of B7-1 costimulatory activity and free PD-L1 that can engage PD-1 to deliver an inhibitory signal.

Figure 3:. Novel interactions of PD-L2 with PD-1 or the BMPR–BMP2/4–RGMb–neogenin complex.

PD-L2 can interact with PD-1, leading to phosphorylation of the PD-1 ITIM and ITSM tyrosines, recruitment and activation of SHP-2, and inhibition of T cell activation. RGMb serves as a co-receptor for BMPs for the type I and type II BMP receptors. The BMPR–BMP2/4–RGMb interaction results in phosphorylation of the BMP receptors and activation of the MAPK, ERK, and SMAD1/5/8 pathways. An RGMb dimer can bridge two Neogenin molecules, forming a RGMb-neogenin complex. RGMb bridging of neogenin engages Rho pathway signaling and cytoskeletal rearrangement. PD-L2 can also interact with RGMb in the BMPR-BMP2-RGMb-neogenin supercomplex and this interaction results in respiratory and mucosal tolerance.