Alternative titles; symbols
HGNC Approved Gene Symbol: VTCN1
Cytogenetic location: 1p13.1-p12 Genomic coordinates (GRCh38) : 1:117,143,587-117,210,927 (from NCBI)
B7H4 belongs to the B7 family (see CD80; 112203) of costimulatory proteins. These proteins are expressed on the surface of antigen-presenting cells and interact with ligands (e.g., CD28; 186760) on T lymphocytes.
By searching an EST database for sequences containing B7 family IgV and IgC domains, followed by screening a placenta cDNA library, Sica et al. (2003) isolated a cDNA encoding B7H4. The predicted 282-amino acid protein, which is 87% identical to the mouse protein, contains a 2-amino acid intracellular domain, a large hydrophobic type I transmembrane region, and an extracellular domain with several N-glycosylation sites and conserved cysteine residues. Northern blot analysis revealed expression of a 1.8-kb transcript in spleen, lung, and thymus, and RT-PCR analysis detected expression in a wide range of tissues. Immunohistochemical and flow cytometric analyses showed expression on activated but not fresh T cells, B cells, monocytes, and dendritic cells.
Independently, Prasad et al. (2003) identified and characterized B7H4, which they termed B7S1. Phosphatidylinositol-specific phospholipase C treatment showed that, unlike other B7 proteins, B7H4 is a glycosyl phosphatidylinositol (GPI)-linked cell membrane protein. Flow cytometric analysis demonstrated expression on B lymphocytes of mouse secondary lymphoid organs, as well as on peritoneal macrophages and bone marrow-derived dendritic cells, and this expression was downregulated after B-cell activation.
Zang et al. (2003) also identified and characterized mouse and human B7H4, which they termed B7X. Phylogenetic comparisons of the B7 family suggested that B7X is most related to B7H3 (605715), while CD80, CD86 (601020), and B7H2 (605717) form a second group, and PDL1 (B7H1; 605402) and PDL2 (605723) form a third group.
Molecular modeling by Sica et al. (2003) suggested that B7H4 does not use CTLA4 or CD28 as a ligand, but that it does display cross-species binding. FACS analysis with a B7H4 fusion protein indicated that T cells express a B7H4 receptor distinct from CTLA4 (123890), ICOS (604558), and PD1 (PDCD1; 600244). Cell-associated, but not soluble, B7H4 inhibited T-cell proliferation, cytokine secretion, and cytotoxic lymphocyte (CTL) induction in vitro by inhibiting cell division and cell cycle progression in the G0/G1 phase. In mice, soluble B7H4 inhibited proliferation and maturation of CD8 (see 186910)-positive T cells and CTL activity. Sica et al. (2003) concluded that B7H4 inhibits T-cell responses at a relatively early stage.
Prasad et al. (2003) determined that B7H4-mediated T-cell inhibition could be reversed by anti-B7H4 blocking antibody, resulting in greater proliferation and IL2 (147680) production.
Flow cytometric analysis by Zang et al. (2003) ruled out interactions between B7H4 and CD28, CTLA4, ICOS, or PD1, but suggested that B7H4 may interact with BTLA (607925).
Krambeck et al. (2006) found that 153 (59%) of 259 tissue specimens from patients with renal cell carcinoma (RCC; 144700) expressed the B7H4 molecule. Tumor cell B7H4 expression was associated with adverse clinical and pathologic features, and patients with these tumors were 3 times more likely to die from RCC compared to patients with tumors lacking B7H4. In addition, 211 (81.5%) specimens showed tumor vasculature endothelial B7H4 expression compared to only 6.5% of normal adjacent renal tissue vessels. Ninety-four (36%) cancer specimens expressed both B7H4 and B7H1 (605402), another coregulatory molecule that inhibits T-cell activity. Expression of both B7H1 and B7H4 was associated with even greater tumor aggressiveness and increased risk of death than expression of either molecule alone. The findings suggested that expression of these molecules by tumor cells may impair host immunity and facilitate tumor progression.
By RT-PCR and FACS analysis and immunofluorescence microscopy, Kryczek et al. (2006) demonstrated that primary ovarian tumor cells express exclusively intracellular B7H4 protein, whereas the majority of ovarian tumor macrophages, but not tumor T cells or blood macrophages, express surface B7H4, possibly by stimulation with tumor-associated IL6 (147620) and IL10 (124092). B7H4+ tumor macrophages suppressed HER2 (ERBB2; 164870)-specific T-cell proliferation and cytotoxicity. Blocking B7H4 expression with specific oligonucleotides improved tumor-associated antigen T-cell responses. Kryczek et al. (2006) concluded that B7H4+ tumor macrophages are a suppressive cell population in ovarian cancer.
By genomic sequence analysis, Zang et al. (2003) determined that the human and mouse B7H4 genes contain 6 exons and span about 70 kb.
Zang et al. (2003) stated that the human B7H4 gene maps to chromosome 1p13.1-p12 and that the mouse gene maps to chromosome 3F3, localizations distinct from those of other B7 family members.
Krambeck, A. E., Thompson, R. H., Dong, H., Lohse, C. M., Park, E. S., Kuntz, S. M., Leibovich, B. C., Blute, M. L., Cheville, J. C., Kwon, E. D. B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc. Nat. Acad. Sci. 103: 10391-10396, 2006. [PubMed: 16798883] [Full Text: https://doi.org/10.1073/pnas.0600937103]
Kryczek, I., Zou, L., Rodriguez, P., Zhu, G., Wei, S., Mottram, P., Brumlik, M., Cheng, P., Curiel, T., Myers, L., Lackner, A., Alvarez, X., Ochoa, A., Chen, L., Zou, W. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203: 871-881, 2006. [PubMed: 16606666] [Full Text: https://doi.org/10.1084/jem.20050930]
Prasad, D. V. R., Richards, S., Mai, X. M., Dong, C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18: 863-873, 2003. [PubMed: 12818166] [Full Text: https://doi.org/10.1016/s1074-7613(03)00147-x]
Sica, G. L., Choi, I.-H., Zhu, G., Tamada, K., Wang, S.-D., Tamura, H., Chapoval, A. I., Flies, D. B., Bajorath, J., Chen, L. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18: 849-861, 2003. [PubMed: 12818165] [Full Text: https://doi.org/10.1016/s1074-7613(03)00152-3]
Zang, X., Loke, P., Kim, J., Murphy, K., Waitz, R., Allison, J. P. B7x: a widely expressed B7 family member that inhibits T cell activation. Proc. Nat. Acad. Sci. 100: 10388-10392, 2003. [PubMed: 12920180] [Full Text: https://doi.org/10.1073/pnas.1434299100]