Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family

Abstract

Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense, and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

“…18,19 However, the gene wide alterations of B7 and TNFR families remain largely unknown in colorectal cancer (CRC). Here, the frequency of B7 and TNFR gene alterations (including mutations, amplifications, and deletions) across 6 studies in colorectal cancer were shown in Figure 1.…”

“…Presently, the co-stimulation pathways mainly involve two major families: the B7 family of immunoglobulins3 and the tumor necrosis factor receptor (TNFR) superfamily. 18,19 The B7 family has 10 reported members, including CD80 (B7-1), CD86 (B7-2), PD-L1 (B7-H1), B7-H2, B7-H3, B7-DC, B7-H4, B7-H5, B7-H6 and B7-H7. 18 These proteins have been proven to regulate both T cell co-stimulatory and co-inhibitory pathways.…”

“…18,19 The B7 family has 10 reported members, including CD80 (B7-1), CD86 (B7-2), PD-L1 (B7-H1), B7-H2, B7-H3, B7-DC, B7-H4, B7-H5, B7-H6 and B7-H7. 18 These proteins have been proven to regulate both T cell co-stimulatory and co-inhibitory pathways. 5,20 The TNFR superfamily proteins are expressed by antigen-presenting cells (APC) or tumor cells, functioning as important secondary signals: OX40L (TNFSF4), CD40 (TNFRSF5), CD70 (TNFSF7), CD137L (TNFSF9), HVEM (TNFRSF14), and GITRL (TNFSF18).…”

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Ligands of B7 protein family are usually expressed by antigen presenting cells and modulate T-lymphocyte activities. This family includes three subgroups: i) B7-1, B7-2, and ICOS-L; ii) Programmed Death Ligand 1 (PD-L1) and 2 (PD-L2); iii) B7-H3, B7x, and HERV-H LTR-associating 2 (HHLA2) [85,86]. Osteosarcoma cells express several members of the B7 family to escape to the immune cells.…”

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…Two well-studied checkpoint receptors on T-cell surfaces are CTLA-4 and PD-1, for which clinically approved inhibitors are now available. 1,2 CTLA-4 and PD-1 can bind to CD80/CD86 and PD-L1/L2, respectively, to counteract activation signals initiated by the T-cell receptor (TCR). Blocking immune checkpoints with “checkpoint inhibitor” therapy was shown to be a powerful approach to release T cell inhibition in preclinical models and is now approved by the FDA for the treatment of certain cancers.…”