The B7 ligand family are cell-surface protein ligands that aid in regulation of the immune response via their interactions with receptors on lymphocytes. They augment the immune response through costimulatory signaling, as is seen during CD28 activation of B and T lymphocytes. On the reverse side, some members of this ligand family attenuate immune responses via coinhibitory pathways, for instance, during inhibition of the CD28 pathway by CTLA-4 and B7-2. There are currently seven known members of this family of ligands. The most well-known are B7-1 (CD80) and B7-2 (CD86), which interact with CD28 and CTLA-4 to regulate T cell signaling. B7 molecules are only expressed on the surface of dendritic cells (DC), macrophages and B cells in the presence of an infection. Manipulation of B7 ligand signals has shown promise as treatment for autoimmune and inflammatory disease and cancer.
B7-1 (CD80) and B7-2 (CD86)
CD28 is the only B7 receptor on the surface of naive T cells. While both B7-1 and B7-2 bind CD28 and co-stimulate T-cell growth, B7-1 is believed to be more involved in sustaining and regulating the activation process after the initial activation signal, while B7-2, which is constitutively expressed on dendritic cells, is believed to be more involved in the initiation of the early immune response. Cancer cells, apart from certain lymphomas, do not express B7-1 molecules and thus are one mechanism used by tumor cells to evade the immune system.
B7-H1 (CD274; PD-L1)
B7-H1, in addition being constitutively expressed on macrophages and DC, can also be induced on activated B and T cells as well as endothelial and epithelial cells. B7-H1, while similar to B7-1 and B7-2, does not bind to CD28, CTLA-4 or ICOS. Instead, it interacts with PD-1 on activated T cells. Cytokine production — specifically IL-2, which is upregulated during T cell activation — is essential for B7-H1 co-stimulation.
B7-H1 has dual functions: co-stimulation of early, naive T cell differentiation and inhibition of activated-effector T cell differentiation, survival and cytokine production to prevent over activation. Additionally, B7-H1 is shown to be upregulated on the surface of a variety of tumor cells, including lung, ovarian and colon tumor cells, as a means of evading immunosurveillance. Higher B7-H1 expression has been shown to correlate with worse prognosis in renal cell carcinoma, esophageal and gastric cancer.
B7-H3 is induced on APCs, dendritic cells, monocytes, NK cells and B cells. While its exact receptors are still unknown, it is believed to co-stimulate the early innate immune system by enhancing secretion of proinflammatory cytokines. It has also been shown to play a role in the later immune response as an inhibitor of effector T cell proliferation and cytokine production (IFN-Ƴ and IL-2). B7-H3 is highly expressed in a range of human solid cancers. In fact, its expression has been reported in 60% to 93% of tumors compared with very limited expression seen in normal healthy tissue. Due to its enhanced expression in tumor cells compared with healthy cells, and the fact its expression directly correlates with poor prognosis and clinical outcomes in a variety of cancers, B7-H3 has the potential to be a powerful biomarker and attractive target for immunotherapy.
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