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IMMUNOBIOLOGY
From the Department of Immunology, Mayo Graduate
and Medical Schools, Mayo Clinic, Rochester, MN; and Human Genome
Sciences, Inc, Rockville, MD.
This report describes a new human B7-like gene designated
B7-H2. Cell surface expression of B7-H2 protein is detected
in monocyte-derived immature dendritic cells. Soluble B7-H2 and
immunoglobulin (Ig) fusion protein, B7-H2Ig, binds activated but not
resting T cells and the binding is abrogated by inducible costimulator
Ig (ICOSIg), but not CTLA4Ig. In addition, ICOSIg stains Chinese
hamster ovary cells transfected with B7-H2 gene. By
suboptimal cross-linking of CD3, costimulation of T-cell proliferation
by B7-H2Ig is dose-dependent and correlates with secretion of
interleukin (IL)-2, whereas optimal CD3 ligation preferentially
stimulates IL-10 production. The results indicate that B7-H2 is a
putative ligand for the ICOS T-cell molecule.
(Blood. 2000;96:2808-2813) Costimulatory interactions between the B7 family
ligands and their receptors play critical roles in the growth,
differentiation, and death of T cells. Engagement of the T-cell
costimulator CD28 by either specific antibodies or its natural ligands
B7-1 and B7-2 increases antigen-specific proliferation of
CD4+ T cells, enhances production of cytokines, induces
maturation of CD8+ effector T cells,1-3 and
promotes T-cell survival.4 Signaling through homologous
CTLA-4 receptor of B7-1 and B7-2 on activated T cells, however, is
thought to deliver a negative signal that inhibits T-cell
proliferation, interleukin (IL)-2 production, and cell cycle
progression.5,6 Although B7-1 and B7-2 share only ~20%
homology in their amino acids, they have similar tertiary structures
and costimulatory functions.7-10
Recent studies indicate that other members of the B7-CD28 family may
also participate in the regulation of cellular and humoral immune
responses. One of the new members is an inducible costimulator (ICOS),
a CD28-like receptor.11 An F44 monoclonal antibody (mAb) against human ICOS costimulates T-cell growth and increases secretion of several cytokines including IL-10, interferon- By searching molecules sharing homologies with the Ig V and Ig C
domains of B7-1, B7-2, and B7-H1 in the NCBI database
(http://www.ncbi.nlm.nih.gov) followed by subsequent cloning and
sequencing, we identified a new B7-like gene designated
B7-H2 (B7 homologue 2).
In addition to an overall structure similarity to B7-1, B7-2, and
B7-H1, B7-H2 binds ICOS and costimulates the proliferation and cytokine
production of human T cells.
Cells
Cloning of human B7-H2 cDNA and construction of
B7-H2Ig fusion proteins
The B7-H2 and Ig fusion gene was created by fusing the cDNA of the extracellular domain of B7-H2 in frame to the CH2-CH3 portion of mouse IgG2a or human IgG1.14 The resulting plasmids were transfected into 293 or CHO cells by Fugene 6 (Boehringer-Mannheim, Mannheim, Germany) according to the manufacturer's instruction. The B7-H2Ig fusion proteins were purified from the culture supernatants of transfected 293 cells grown in serum-free media (Gibco) by a protein G-Sepharose column (Pharmacia, Uppsala, Sweden). Human ICOSIg, B7-H1Ig, and CTLA4Ig were prepared as described previously.14 Flow cytometry analysis To prepare antisera, BALB/c mice were immunized with purified B7-H2/mouse Ig fusion proteins (B7-H2mIg) in complete Freund adjuvant (Sigma, St Louis, MO) and boosted 3 times with B7-H2mIg in incomplete Freund adjuvant. Sera were collected 10 days after the last boost. The specificities of antisera were determined in enzyme-linked immunosorbent assay (ELISA) against B7-H2Ig and by FACS staining against 293 cells transfected with the pcDNA3.1 plasmid containing the B7-H2 full-length cDNA (phB7-H2). Prebleed mouse sera were used as controls. To detect human B7-H2 expression, DC at 1 × 106 were incubated with anti-B7-H2 antiserum (1:1000) or control serum (1:1000) in FACS buffer (phosphate-buffered saline [PBS], 3% fetal calf serum [FCS], 0.02% NaN3) at 4°C for 30 minutes. The cells were washed and further incubated with fluorescein isothiocyanate (FITC)-conjugated goat antimouse IgG (BioSource, Camarillo, CA) for 30 minutes at 4°C. Fluorescence was analyzed by a FACSCaliber flow cytometry (Becton Dickinson, Mountain View, CA) with Cell Quest software (Becton Dickinson).To detect the expression of the counter-receptor of B7-H2 in T cells, nylon wool-purified T cells were cultured either unstimulated or stimulated with 5 µg/mL phytohemagglutinin (PHA; Sigma) for 1 to 3 days as indicated. The cells were then stained by B7-H2Ig and analyzed by FACS. CHO cell lines expressing surface B7-H2 were also established by selection of neomycin-resistant clones of cells transfected with the phB7-H2 plasmid. For indirect immunofluorescence staining, cells were first stained with anti-B7-H2 antiserum (1:1000) or ICOSIg for 30 minutes and further incubated with FITC-conjugated goat antimouse or antihuman IgG antibodies, respectively. Normal serum or purified human IgG1 were used as controls. T-cell proliferation and cytokine assays Enrichment of T cells was performed by passing nonadherent PBMCs of a healthy donor through nylon wool columns (Robbins Scientific Co, Sunnyvale, CA) as described previously.14 For the costimulation assay, flat-bottomed 96-well microplates were first coated with 100 µL of anti-CD3 mAb of indicated doses at 4°C overnight. After intensive washing with PBS, the plates were further coated with B7-H2Ig or control IgG at 37°C for 4 hours and then the purified T cells were added to the wells at 2 × 105 cells/well in triplicate. The cells were cultured for 72 hours and 3H-TdR at 1.0 µCi/well was added during the last 15 hours. The incorporation of 3H-TdR was counted by MicroBeta Trilux liquid scintillation counter (Wallac, Finland). To detect cytokines, supernatants were collected at 24, 48, and 72 hours of the cultures and the concentrations of IL-2 and IL-10 were determined by sandwich ELISA methods (PharMingen, San Diego, CA) according to manufacturer's instructions. B7-H1Ig in immobilized form and an anti-CD28 mAb (PharMingen) in soluble form were included for comparison. Polymyxin B at 10 µg/mL was also incorporated to completely neutralize potential endotoxin contamination.
Molecular cloning and expression of human B7-H2 gene Search of the NCBI database against amino acid sequences of human B7-1, B7-2, and B7-H1 revealed that the 5'-end of the KIAA0653 protein shared ~20% homology to known B7 members. However, the KIAA0653 sequence encodes a putative protein with 558 amino acids and its 3'-end amino acid sequence does not have structure similarity to the members of the B7 family. Sequencing analysis of the cDNA isolated from human DCs by reverse transcriptase (RT)-PCR, however, revealed a different nucleic acid sequence from codon 1028. As a result, a stop codon TGA was identified. We have thus identified a new cDNA species encoding a putative protein with 302 amino acids, designated as B7-H2. B7-H2 encodes a glycosylated, type I protein consisting of Ig V-like domain, Ig C-like domain, hydrophobic transmembrane domain and cytoplasmic tail (Figure 1A). Four structural cysteines (as labeled by stars in Figure 1B), which are apparently involved in forming the disulfide bonds of the Ig V and Ig C domains, are well conserved in all B7 members (Figure 1B). B7-H2 shares an overall homology to B7-1 (24% amino acid identity), B7-2 (21%), and B7-H1 (21%) based on analysis using the multiple sequence alignment program of McVector 6.5 software (Figure 1B). Similar analysis shows that human B7-H2 and mouse B7h/B7RP-1 share ~ 46% of homology, indicating that B7-H2 may be a human homologue of mouse B7h/B7RP-1.
To determine whether B7-H2 is expressed as a membrane-bound
surface protein, we first constructed a plasmid containing the cDNA of
the extracellular region of B7-H2 fused in frame with the Fc portion of
the human IgG1. The resulting plasmid was transfected into 293 cells
and the B7-H2Ig fusion protein was purified by protein G column from
the culture supernatants. Antisera against B7-H2 were prepared by
immunization of BALB/c mice with the purified B7-H2mIg. The antisera
are specific for B7-H2 because these sera did not stain CHO cells
transfected with B7-1, B7-2, or B7-H1 (data not shown) but stained
B7-H2. FACS analysis indicates that although there is no
substantial expression of unfractionated PBMCs (data not shown), DCs
generated from adherent PBMCs in the presence of GM-CSF and IL-4
express B7-H2 on their surface (Figure 2;
Binding of B7-H2 to ICOS molecule on activated T cells We have examined the expression of the counter-receptor of B7-H2 by FACS analysis. Indirect immunoflurorescence staining using B7-H2Ig showed that the counter-receptor did not express on resting PBMCs. However, T cells that were stimulated by PHA expressed high levels of counter-receptor of B7-H2. The expression can be detected 24 hours after stimulation and is sustained up to 72 hours (Figure 3A). Similar results were also obtained using T cells that were activated with anti-CD3 plus anti-CD28 mAbs. Therefore, the counter-receptor of B7-H2 appears to be inducible in T cells.
Two costimulatory receptors, CTLA-4 and ICOS, can be induced on activated T cells.2,11 We therefore examined whether soluble ICOSIg or CTLA4Ig can block the binding of B7-H2Ig to activated T cells. As shown in Figure 3B, the binding activity of B7-H2Ig to PHA-activated T cells can be completely abrogated by the inclusion of ICOSIg, but not CTLA4Ig, indicating that the competition of ICOSIg in our assay is specific. This result suggests that ICOS is a potential counter-receptor for B7-H2. To further confirm this finding, we exam-ined whether CHO cells, a B7-H2 negative cell line, could confer ICOSIg binding activity after transfection to express B7-H2 gene. We constructed a plasmid, phB7-H2, in which the full-length cDNA of human B7-H2 was inserted into a pcDNA3.1 vector. As shown in Figure 3C, CHO cells transfected with phB7-H2 (CHO/B7-H2) could be stained by ICOSIg. As a positive control, anti-B7-H2 can also bind to CHO/B7-H2 but not to CHO/mock cells. Our results thus indicate that B7-H2 binds ICOS on T cells. B7-H2 costimulates T cell proliferation To determine costimulatory function of B7-H2, we purified T cells from human PBMC of healthy donors and stimulated them with B7-H2Ig in the presence of suboptimal doses of an anti-CD3 mAb. T-cell proliferation was determined by incorporation of 3H-TdR after 3-day culture. B7-H2Ig, when immobilized on plastic plates, enhanced T-cell proliferation up to 5-fold compared to the control Ig in the presence of 40 ng/mL of immobilized anti-CD3 mAb (Figure 4A). The costimulatory effects of the B7-H2-Ig were dose-dependent (Figure 4B). In the absence of anti-CD3, B7-H2Ig in concentrations of 5 µg/mL had no effect on T-cell proliferation (Figure 4A). Our results demonstrate that B7-H2 engagement costimulates T cell response.
IL-2 and IL-10 secretion by B7-H2 costimulation It has been reported that stimulation of T cells by optimal cross-linking of OKT3 in the presence of a F44 mAb to ICOS can preferentially induce IL-10 but not IL-2 production.11 To examine whether B7-H2Ig could do so, the levels of IL-2 and IL-10 in the T-cell culture supernatants by the stimulation of B7-H2Ig and an optimal dose of an anti-CD3 mAb (500 ng/mL) were determined by sandwich ELISA. Our preliminary experiments demonstrated that T cells proliferated vigorously at this dose of anti-CD3 mAb (data not shown). Immobilized B7-H2Ig moderately increases IL-10 secretion at the 48-hour point. In contrast, T cells costimulated by B7-H2Ig in the presence of a suboptimal dose (40 ng/mL) of anti-CD3 mAb had slightly increased levels of IL-2 but not IL-10. IL-10 did not increase throughout the 72 hours, whereas IL-2 was moderately elevated at 48 and 72 hours (Figure 5). As expected, both B7-H1Ig and anti-CD28 mAb costimulated IL-10 production disregarding the doses of anti-CD3.14 Our results thus suggest that different strengths of CD3 engagement can affect the pattern of cytokine secretion by B7-H2 engagement.
We have identified a human B7-like molecule and provide evidence that this molecule is a putative ligand for a recently described T-cell molecule ICOS. Similar to other B7 family members, the extracellular region of the B7-H2 protein has 4 conserved structural cysteines that are believed to form Ig V- and IgC-like domain.7-10 In addition, B7-H2 has a conserved tyrosine residue in the Ig V-like domain at the position of 80, which is identical to that of B7-1 at position 87, B7-2 at position 82, and B7-H1 at position 81 (Figure 1B). Despite a structural similarity, B7-H2 does not seem to bind the receptors of B7-1 and B7-2. B7-H2Ig binds strongly to activated but not resting T cells (Figure 3A). This observation precludes the possibility that B7-H2 is a ligand for CD28 because high levels of CD28 can be detected in the resting T cells.1,2 FACS analysis showed that ICOSIg, but not CTLA4Ig abrogated the binding of B7-H2 to activated T cells (Figure 3B). In addition, ICOSIg stained CHO cells transfected with the B7-H2 cDNA (Figure 3C). Taken together, our results support that B7-H2 is a ligand for ICOS. Final confirmation of B7-H2 as the ligand for ICOS, however, awaits extensive studies including functional comparison of B7-H2Ig and anti-ICOS antibody. By alignment analysis, B7-H2 shares ~46% identity at amino acid level to B7h/B7RP-1, a recently described B7-like protein of mouse origin.12,13 This raises the possibility that B7h/B7RP-1 is a mouse homologue of B7-H2. It was shown that B7h binds weakly to activated, but not resting T cells,12 supporting this possibility. In mice, B7h/B7RP-1 can be detected on the surface of B cells, macrophages, and activated T cells but not in CD80+, Dec205+, and CD11c+ cells,13 suggesting that B7h/B7RP-1 is not constitutively expressed on DCs. Our result, however, showed that B7-H2 was readily detected in monocyte-derived human DCs that were generated by GM-CSF and IL-4 (Figure 2). This result may be interpreted as the induction of B7-H2 by in vitro culture condition. Alternatively there may be a different expression pattern of B7-H2 in human and mouse tissues. In addition, the expression of B7-H2 can be down-regulated by exposure to LPS (Figure 2B) and the functional significance of this finding is unclear. Costimulatory functions of B7-H2 were demonstrated by the ability that immobilized B7-H2Ig could amplify T-cell proliferation in the presence of suboptimal doses of anti-CD3 (Figure 4). It has been reported that stimulation of T cells with the anti-ICOS mAb F44 preferentially induces IL-10 production.11 We have found that B7-H2Ig is capable of inducing a moderate increase of IL-10 in the culture (Figure 5A). However, this effect was only observed when a high dose, but not a suboptimal dose, of anti-CD3 mAb was used. In the presence of suboptimal doses of anti-CD3 mAb, B7-H2 costimulation slightly increases the production of IL-2 but not IL-10 (Figure 5B). Because suboptimal doses of anti-CD3 mAb mimic more closely to physiologic interaction between MHC-peptides and T-cell receptor-CD3 complexes, our results suggest that IL-10 production under antigen-specific interactions in vivo may not be a dominant event. Our study thus identifies a putative ligand for ICOS T-cell costimulatory molecule and suggests a regulatory function of B7-H2/ICOS interaction in the cell-mediated immune responses.
During the review process of this manuscript, Ling and colleagues16 reported the sequence of a B7-like molecule called GL50 that is identical to human B7-H2.
We thank Dallas Flies and Beth Martin for their excellent technical assistance and Kathy Jensen for editing the manuscript.
Submitted February 8, 2000; accepted June 8, 2000.
Supported in part by Mayo Foundation, and by National Institutes of Health (NIH) grants CA79915 and CA15083. G.Z. and K.T. are supported by NIH postdoctoral training grant CA09127 and US Army breast cancer research fellowship, respectively.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Lieping Chen, Department of Immunology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: chen.lieping{at}mayo.edu.
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S.-C. Wong, E. Oh, C.-H. Ng, and K.-P. Lam Impaired germinal center formation and recall T-cell-dependent immune responses in mice lacking the costimulatory ligand B7-H2 Blood, August 15, 2003; 102(4): 1381 - 1388. [Abstract] [Full Text] [PDF]
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J. Yagi, Y. Arimura, U. Dianzani, T. Uede, T. Okamoto, and T. Uchiyama Regulatory Roles of IL-2 and IL-4 in H4/Inducible Costimulator Expression on Activated CD4+ T Cells During Th Cell Development J. Immunol., July 15, 2003; 171(2): 783 - 794. [Abstract] [Full Text] [PDF]
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S. Kurosawa, A. C. Myers, L. Chen, S. Wang, J. Ni, J. R. Plitt, N. M. Heller, B. S. Bochner, and R. P. Schleimer Expression of the Costimulatory Molecule B7-H2 (Inducible Costimulator Ligand) by Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 563 - 573. [Abstract] [Full Text] [PDF]
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D. Trabattoni, M. Saresella, M. Biasin, A. Boasso, L. Piacentini, P. Ferrante, H. Dong, R. Maserati, G. M. Shearer, L. Chen, et al. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression Blood, April 1, 2003; 101(7): 2514 - 2520. [Abstract] [Full Text] [PDF]
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F. Bennett, D. Luxenberg, V. Ling, I-M. Wang, K. Marquette, D. Lowe, N. Khan, G. Veldman, K. A. Jacobs, V. E. Valge-Archer, et al. Program Death-1 Engagement Upon TCR Activation Has Distinct Effects on Costimulation and Cytokine-Driven Proliferation: Attenuation of ICOS, IL-4, and IL-21, But Not CD28, IL-7, and IL-15 Responses J. Immunol., January 15, 2003; 170(2): 711 - 718. [Abstract] [Full Text] [PDF]
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H.-W. Mittrucker, M. Kursar, A. Kohler, D. Yanagihara, S. K. Yoshinaga, and S. H. E. Kaufmann Inducible Costimulator Protein Controls the Protective T Cell Response Against Listeria monocytogenes J. Immunol., November 15, 2002; 169(10): 5813 - 5817. [Abstract] [Full Text] [PDF]
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D. Mason, P. Andre, A. Bensussan, C. Buckley, C. Civin, E. Clark, M. de Haas, S. Goyert, M. Hadam, D. Hart, et al. CD antigens 2002 Blood, May 15, 2002; 99(10): 3877 - 3880. [Full Text] [PDF]
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S. Khayyamian, A. Hutloff, K. Buchner, M. Grafe, V. Henn, R. A. Kroczek, and H. W. Mages ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells PNAS, April 30, 2002; 99(9): 6198 - 6203. [Abstract] [Full Text] [PDF]
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V. Ling, P. W. Wu, J. S. Miyashiro, S. Marusic, H. F. Finnerty, and M. Collins Differential Expression of Inducible Costimulator-Ligand Splice Variants: Lymphoid Regulation of Mouse GL50-B and Human GL50 Molecules J. Immunol., June 15, 2001; 166(12): 7300 - 7308. [Abstract] [Full Text] [PDF]
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J. L. Riley, P. J. Blair, J. T. Musser, R. Abe, K. Tezuka, T. Tsuji, and C. H. June ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement J. Immunol., April 15, 2001; 166(8): 4943 - 4948. [Abstract] [Full Text] [PDF]
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S.-Y. Tseng, M. Otsuji, K. Gorski, X. Huang, J. E. Slansky, S. I. Pai, A. Shalabi, T. Shin, D. M. Pardoll, and H. Tsuchiya B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells J. Exp. Med., April 2, 2001; 193(7): 839 - 846. [Abstract] [Full Text] [PDF]
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H. Tamura, H. Dong, G. Zhu, G. L. Sica, D. B. Flies, K. Tamada, and L. Chen B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function Blood, March 15, 2001; 97(6): 1809 - 1816. [Abstract] [Full Text] [PDF]
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S. Wang, G. Zhu, K. Tamada, L. Chen, and J. Bajorath Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function J. Exp. Med., April 15, 2002; 195(8): 1033 - 1041. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, and IL-4, but not
IL-2 in the presence of optimal doses of anti-CD3
antibody.
in the 3T3 fibroblast line and the
increase of B7h/B7RP-1 messenger RNA (mRNA) is also observed in
nonlymphoid tissues exposed to lipopolysaccharide (LPS).
LPS). Induction of DC maturation by stimulation with LPS led to a
high level expression of B7-2 (Figure 
