B7-H7 Can Have Multiple Effects on T Cell Activity
B7-H7 Can Mediate T Cell Co-stimulatory and Co-inhibitory Effects
B7-H7, also known as HHLA2, is the only member of the B7 family that is found in humans but not in mice. Unlike other B7 family members, B7-H7 has three extracellular immunoglobulin-like domains with an IgV-IgC-IgV arrangement. Similar to B7-H3, B7-H7 has been reported to have both co-stimulatory and co-inhibitory functions.1 While B7-H7 on antigen-presenting cells (APCs) has been shown to bind to CD28H/TMIGD2 on naïve T cells and promote T cell proliferation and cytokine production, B7-H7 has also been shown to inhibit T cell proliferation and reduce cytokine secretion.1-3 One explanation for these seemingly contradictory findings is that B7-H7 has two receptors with CD28H being a co-stimulatory receptor that is gradually lost during T cell activation, which allows a second, unidentified co-inhibitory receptor to become the preeminent B7-H7 receptor.3 B7-H7 is expressed in a number of human cancers and its expression typically correlates with metastasis and a poor prognosis, suggesting that tumor cell-expressed B7-H7 interacts with a B7-H7 co-inhibitory receptor expressed on activated T cells to inhibit the anti-tumor immune response.4
B7-H7 May Bind to Two Different Receptors with Opposing Effects on T Cell Activity
B7-H7/HHLA2 can mediate T cell co-stimulatory effects by binding to CD28H/ TMIGD2 but may also mediate T cell co-inhibitory effects by binding to an unidentified receptor. B7-H7/HHLA2 is expressed on antigen-presenting cells (APCs) and binds to the T cell-expressed receptor, CD28H, to stimulate T cell proliferation and cytokine production. Conversely, B7-H7/HHLA2 has also been shown to function as a T cell co inhibitory molecule, suggesting that B7-H7/HHLA2 may interact with a second unidentified receptor that inhibits T cell activity.
Analysis of the Binding of R&D Systems Recombinant Human B7-H7 and CD28H Proteins
B7-H7/HHLA2 Binds to CD28H/TMIGD2. Recombinant Human CD28H/TMIGD2 Fc Chimera (R&D Systems, Catalog # 8316-TR) was coated on a plate at 0.125 μg/mL and the indicated concentrations of Biotinylated Recombinant Human B7-H7/HHLA2 Fc Chimera (R&D Systems, Catalog # BT8084) were added. Recombinant Human B7-H7/HHLA2 bound with an ED50 of 0.025-0.125 μg/mL.
Assessment of the Bioactivity of R&D Systems Recombinant Human B7-H7 Protein
B7-H7/HHLA2 Inhibits Anti-CD3-induced IL-2 Secretion by Human T Cells. Human T cells were incubated with an immobilized Mouse Anti-Human CD3 epsilon Monoclonal Antibody (R&D Systems, Catalog # MAB100) and the indicated concentrations of Recombinant Human B7-H7/HHLA2 Fc Chimera (R&D Systems, Catalog # 8084-B7).IL-2 secretion was measured in cell culture supernatants using the Human IL-2 QuantikineTM ELISA Kit (R&D Systems, Catalog # D2050).The ED50 for this effect is typically 0.075-0.75 μg/mL in the presence of a Goat Anti-Human IgG Fc Polyclonal Antibody (R&D Systems, Catalog # G-102-C).
Zhu, Y. et al. (2013) B7-H5 costimulates human T cells via CD28H. Nat. Comm. 4:2043. PMID: 23784006.
Zhao, R. et al. (2013) HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc. Natl. Acad. Sci. USA 110:9879. PMID: 23716685.
Wang, J. et al. (2014) Biofunctions of three new B7 family members. J. Immunol. 192:12611.
Ni, L. & C. Dong (2017) New B7 family checkpoints in human cancers. Mol. Cancer Ther. 16:1203. PMID: 28679835.