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B7-H3 Has Multiple Effects on T Cell Activity

B7-H3 Can Mediate T Cell Co-stimulatory and Co-inhibitory Effects

B7-H3 is one of several members of the B7 family that binds to a currently unidentified receptor expressed on activated T cells.1, 2 In humans, there are two isoforms of B7-H3, one with a single IgV-like and IgC-like domain, and a second, more common isoform that has a tandem repeat of the IgV-like and IgC-like domains.2, 3 B7-H3 was initially characterized to be a T cell co-stimulatory molecule due to its ability to promote both CD4+ and CD8+ T cell proliferation and enhance IFN-gamma secretion, but it was subsequently found to have T cell inhibitory functions as well.1, 4, 5 B7-H3 was shown to inhibit T cell proliferation, Th1 responses, and IL-2 and IFN-gamma secretion, as well as natural killer (NK) cell activity.4-7 These conflicting results have led to the hypothesis that B7-H3 may bind to two different receptors, one that stimulates T cell activity and one that inhibits T cell activity. In cancer, B7-H3 is overexpressed in a number of different tumor tissues and high levels of B7-H3 correlate with a poor prognosis and an increased potential for metastasis.8, 9 In addition, a soluble form of B7-H3 can be generated by ADAM-mediated ectodomain shedding, and serum levels of soluble B7-H3 are significantly higher in patients with different types of cancer.6 In tumor-bearing mice, a blocking antibody against B7-H3 has been shown to enhance anti-tumor immune responses, suggesting that B7-H3 may be a future target for immunotherapy.10, 11

B7-H3 May Bind to Two Different Receptors with Opposing Effects on T Cell Activity

Binding of B7-H3 with an unidentified receptor(s) can have both T cell co-stimulatory and co-inhibitory effects.

B7-H3 binds to an unidentified receptor and can mediate both T cell co-stimulatory and co-inhibitory effects. Two human isoforms of B7-H3 (2Ig-B7-H3 and 4Ig B7-H3) have been described. Some studies have shown B7-H3 to be a T cell co-stimulatory molecule, while others have demonstrated that it can function as a T cell co-inhibitory molecule. Although the receptor(s) for B7-H3 have yet to be identified, the data suggests that like B7-1/CD80 and B7-2/CD86, B7-H3 may have more than one receptor, one that stimulates and one that inhibits T cell activity. B7-H3 has been reported to be expressed in several human tumors and its expression typically correlates with a poor prognosis.

Assessment of the Bioactivity and Purity of R&D Systems B7-H3 Proteins

Analysis of the effect of R&D Systems Recombinant Cynomolgus Monkey B7-H3 on activated T cells.

B7-H3 Inhibits IFN-gamma Secretion by Anti-CD3-Stimulated Human T Cells. Human T cells were treated with an immobilized Mouse Anti-Human CD3 epsilon Monoclonal Antibody (R&D Systems, Catalog # MAB100) and the indicated concentrations of Recombinant Cynomolgus Monkey B7-H3 (R&D Systems, Catalog # 9426-B3). IFN-gamma secretion was measured using the Human IFN-gamma QuantikineTM ELISA Kit (R&D Systems, Catalog # DIF50). The ED50 for this effect is typically 1-10 μg/mL.

Purity of Recombinant Human B7-H3 assessed by capillary electrophoresis (CE-SDS) on the Maurice system.

Assessment of the Purity of Recombinant Human B7-H3 by CE-SDS on the MauriceTM System. The purity of Avi-tag Biotinylated Recombinant Human B7-H3 His tag (R&D Systems, Catalog # AVI2318) was assessed by capillary electrophoresis (CE)-SDS on the Maurice System under reducing (R) and nonreducing (NR) conditions and visualized in Compass for iCE software. The gel view is shown as an inset with the relative migration time (RMT) on the electropherogram shown on the far right-hand side of the gel. 

References

1. Chapoval, A.I. et al (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat. Immunol. 2 269 PMID: 11224528

2. Sun, M. et al (2002) Characterization of mouse and human B7-H3 genes. J. Immunol. 168 6294 PMID: 12055244

3. Steinberger, P. et al (2004) Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains J. Immunol. 172 2352 PMID: 14764704

5. Prasad, D.V. et al (2004) Murine B7-H3 is a negative regulator of T cells. J. Immunol. 173 2500 PMID: 15294965

6. Ni, L. & C. Dong (2017) New B7 family checkpoints in human cancers. Mol. Cancer Ther. 16 1203 PMID: 28679835

7. Marin-Acevedo, J.A. et al (2018) Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 11 39 PMID: 29544515