B7-H3: A costimulatory molecule for T cell activation and IFN-γ production

Abstract

We describe here a newly identified member of the human B7 family, designated B7 homolog 3 (B7-H3), that shares 20-27% amino acid identity with other B7 family members. B7-H3 mRNA is not detectable in peripheral blood mononuclear cells, although it is found in various normal tissues and in several tumor cell lines. Expression of B7-H3 protein, however, can be induced on dendritic cells (DCs) and monocytes by inflammatory cytokines and a combination of phorbol myristate acetate (PMA) + ionomycin. Soluble B7-H3 protein binds a putative counter-receptor on activated T cells that is distinct from CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS) and PD-1. B7-H3 costimulates proliferation of both CD4+ and CD8+ T cells, enhances the induction of cytotoxic T cells and selectively stimulates interferon gamma (IFN-gamma) production in the presence of T cell receptor signaling. In contrast, inclusion of antisense B7-H3 oligonucleotides decreases the expression of B7-H3 on DCs and inhibits IFN-gamma production by DC-stimulated allogeneic T cells.Thus, we describe a newly identified costimulatory pathway that may participate in the regulation of cell-mediated immune responses.

Mouse B7-H3 induces antitumor immunity

“…BE311080), which encoded a full-length B7-like cDNA sequence with extensive similarity to the subsequently published sequence of human B7-H3. 12 The cDNA sequence of clone #3483288 encoded a 316 amino-acid (aa) residue type I membrane protein, consisting of a 29 aa signal peptide, single 112 aa IgV-like and 106 aa IgC-like extracellular domains, a 24 aa transmembrane region, and a short 45 aa cytoplasmic tail (Figure 1a). The encoded protein contains four potential N-glycosylation sites at aa positions 91, 104, 189, and 215 of the immature sequence.…”

“…11 The newest member of the B7 family, designated B7-H3, was cloned from a human dendritic cell-derived cDNA library. 12 It is widely expressed in various normal tissues, and its expression can be induced on monocytes and DCs. It appears to bind a counter-receptor on activated T cells that is distinct from CD28, CTLA-4, ICOS, and PD-1.…”

“…B7-H3 costimulates the proliferation of CD4 + and CD8 + T cells, enhances the induction of cytotoxic T cells, and selectively enhances IFN-g expression, with modest effects on TNF-a production. 12 Thus, B7-H3 is proposed to complement ICOS signaling by regulating Th1 and CTL responses.…”

“…However, unlike B7-1, it is a poor costimulator of naïve T cells, and is predicted to play a critical role in the regulation of T-cell responses after the initial priming stage. 12 In the present study, we test the notion that B7-H3 can induce antitumor immunity by determining whether intratumoral gene transfer of mouse B7-H3 expression plasmids is able to eradicate established EL-4 lymphomas.…”

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

“…8,11 Immature DC undergo a maturation process after they encounter antigens, and subsequently migrate to lymphoid tissue to prime naive T cells. 12,13 Induction of effective antitumor response requires DC to present tumor antigen, 14 but tumor cells often have limited expression of MHC antigens and costimulatory molecules, [15][16][17] and also tumor cells can produce immune inhibitory factors that inhibit DC maturation and migration. 18,19 It has been shown that the quantity of DC within tumors of a variety of histological types are correlated with prognosis, 20,21 and that DC which reside within the tumor are immature.…”