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CD200 Human CD200 and Human Herpesvirus-8 Down-Regulation Of Down-Regulation of Basophil Function by Human CD200 and Human Herpesvirus-8 CD200 This information is current as Ikuo Shiratori, Masao Yamaguchi, Maho Suzukawa, of September 26, 2021. Kazuhiko Yamamoto, Lewis L. Lanier, Takashi Saito and Hisashi Arase J Immunol 2005; 175:4441-4449; ; doi: 10.4049/jimmunol.175.7.4441 http://www.jimmunol.org/content/175/7/4441 Downloaded from References This article cites 37 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/175/7/4441.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Down-Regulation of Basophil Function by Human CD200 and Human Herpesvirus-8 CD2001 Ikuo Shiratori,*† Masao Yamaguchi,‡ Maho Suzukawa,‡ Kazuhiko Yamamoto,‡ Lewis L. Lanier,§ Takashi Saito,¶ and Hisashi Arase2*† Human and rodent CD200 are recognized by the inhibitory CD200R, and these molecules play an important role in the regulation of the immune system. Several viruses, such as human herpesvirus-6 (HHV-6), HHV-7, and HHV-8, possess a CD200 homologue, suggesting that these viruses regulate the immune response via CD200R. In this study, we analyzed the effect of human CD200 and the viral CD200 homologues on human CD200R-expressing cells. We found that human CD200R is predominantly expressed on basophils in amounts higher than on other human peripheral blood leukocytes. Furthermore, the viral CD200 homologues as well as human CD200 were recognized by human CD200R, and the activation of basophils was down-regulated by these CD200 proteins. These results suggested that CD200R is an important regulatory molecule of basophil activation. In addition, the Downloaded from presence of CD200 homologues on several viruses suggests a potentially unique relationship between basophil function and viral infection. The Journal of Immunology, 2005, 175: 4441–4449. mmune cells express inhibitory receptors to prevent damage for an inhibitory Ly49 receptor in certain MCMV-susceptible to self. Many of the inhibitory receptors recognize broadly mouse strains (10). Similarly, human CMV acquired UL18 as a expressed self-proteins, such as MHC class I (1, 2). CD200R ligand for the inhibitory CD85J (leukocyte inhibitory receptor/Ig- I http://www.jimmunol.org/ (3) is an inhibitory receptor that possesses a tyrosine phosphatase- like transport) receptor (11). These decoy ligands for inhibitory recruiting inhibitory motif in its cytoplasmic domain (3, 4). receptors may play an important role, allowing the viruses to evade CD200R is primarily expressed on leukocytes of the myeloid lin- the immune system and potentially cause persistent infectious dis- eage, and it recognizes CD200, which is broadly expressed on a eases (12). Interestingly, herpesviruses, such as human herpesvi- variety of cell types (3, 5, 6). In mice, disruption of the gene rus-6 (HHV-6), HHV-7, and HHV-8 (13–15), and poxviruses, in- encoding CD200 led to expansion of the macrophage and granu- cluding myxoma virus and shope fibroma virus, possess genes locyte populations in the spleen and the macrophage population in encoding proteins with homology to CD200 (16, 17). Although mesenteric lymph nodes (7). Furthermore, CD200-deficient mice amino acid homologies between human CD200 and these viral showed rapid onset of experimental autoimmune encephalomyeli- by guest on September 26, 2021 CD200 homologues are Ͻ40%, this level of similarity is sufficient tis (7). Administration of CD200-Ig fusion protein, which func- to permit binding to the inhibitory CD200R. In fact, the CD200 tions as an agonist for the inhibitory CD200R, suppressed allograft homologue of HHV-8 (HHV-8 CD200) has been described as a rejection and collagen-induced arthritis in animal models (8, 9). These data suggested that recognition of CD200 by an inhibitory decoy ligand for CD200R (18, 19). However, the effect of the CD200R plays an important role in regulating immune responses. HHV-8 CD200 on CD200R-expressing human cells has remained Several viruses that persistently infect the host have acquired unclear, and there are conflicting reports in the literature (18, 19). ligands for inhibitory receptors, presumably to suppress an im- In the present study we show that basophils are a major mune response against these pathogens. For example, murine CD200R-positive population in human peripheral blood. Further- CMV (MCMV)3 has evolved m157, which functions as a ligand more, we show that not only the HHV-8 CD200, but also the CD200 homologues of HHV-6 (HHV-6 CD200) and HHV-7 (HHV-7 CD200), are recognized by CD200R and that activation of *Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; †Precursory Research for Embryonic Science and Tech- basophils is down-regulated by recognizing human CD200 and nology, Japan Science and Technology Agency, Saitama, Japan; ‡Department of Al- HHV-8 CD200. These findings suggest that CD200R regulates lergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; §Department of Microbiology and Immunology and the Cancer Research In- basophil activation, and the viral CD200 homologues are involved stitute, University of California, San Francisco, CA 94143; ¶Laboratory for Cell Sig- in the regulation of basophil-dependent immune responses. naling, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan Received for publication May 24, 2005. Accepted for publication July 20, 2005. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance Materials and Methods with 18 U.S.C. Section 1734 solely to indicate this fact. cDNA preparation 1 This work was supported by a Grant-in-Aid for Scientific Research from the Min- CD200 homologues of HHV-7 (U85) and HHV-8 (K14) were cloned using istry of Education, Science, and Culture, Japan (to T.S. and H.A.), and the Uehara PCR from genomic DNA of HHV-7 and HHV-8 (provided by Dr. L. Memorial Foundation (to H.A.). L.L.L. is an American Cancer Society Research Professor and is supported by National Institutes of Health Grant CA89294. Coscoy, University of California, Berkeley, CA). The CD200 homologue of HHV-6 (U85) was cloned using PCR directly from supernatant contain- 2 Address correspondence and reprint requests to Dr. Hisashi Arase, Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, 3-1 ing HHV-6 virus (strain SF; provided by Dr. L. Coscoy). The GenBank/ Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail address: [email protected] EMBL/DDBJ accession numbers of HHV-6, HHV-7, and HHV-8 are u.ac.jp AB190768, HHU43400, and AF367765, respectively. Human CD200 and 3 CD200R were cloned using PCR from cDNA generated from human Abbreviations used in this paper: MCMV, murine CMV; HHV, human herpesvirus; ϩ HHV-6 CD200, CD200 homolog of HHV-6; HHV-7 CD200, CD200 homolog of PBMC-derived poly(A) RNA. Mouse CD200R was cloned from cDNA ϩ HHV-7; HHV-8 CD200, CD200 homolog of HHV-8; PIPES-A, PIPES-Albumin. generated from mouse spleen-derived poly(A) RNA. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 4442 REGULATION OF BASOPHIL FUNCTION BY CD200 Ig fusion proteins GAGCTGCGTGTG-3Ј; antisense primer, 5Ј-CGTAGATGGGCACAGT GTGG-3Ј; GAPDH: sense primer, 5Ј-ATGCTGGCGCTGAGTACGTC- cDNA fragments corresponding to the extracellular domains of human 3Ј; antisense primer, 5Ј-CAGGGGTGCTAAGCAGTTGGT-3Ј; and human CD200R (aa residues 25–267), mouse CD200R (aa residues 26–238), hu- CD200R: sense primer, 5Ј-CTTCCTGTTCCAGGTGCCAAA-3Ј; anti- man CD200 (aa residues 56–263), and HHV8-CD200 (aa residues 25–226) sense primer, 5Ј-GCCTCAGATGCCTTCACCTTG-3Ј. ␤-Actin and were cloned into a unique XhoI site of a modified pME18S expression GAPDH were used to standardize the relative amounts of CD200 tran- vector carrying the human CD150 leader segment and the Fc segment of scripts in the different cell populations. Comparable results were obtained human IgG1 (20). COS-7 cells were transiently transfected by using when either ␤-actin or GAPDH was used for normalization of the data. 293fectin (InvitroGen) with these expression vectors to generate Ig fusion proteins. After 72 h, the culture supernatants were collected, and the Histamine release assay amounts of Ig fusion protein were measured using standard ELISA meth- ods. For some experiments, human CD200-Ig and HHV-8-CD200-Ig fu- Histamine release from basophils was analyzed as previously described sion proteins were further purified using protein A-coupled Sepharose col- (22). Purified basophils (2.0–4.0 ϫ 105) were incubated with 10 ␮g/ml umns (Amersham Biosciences) by standard methods. human CD200-Ig, HHV-8 CD200-Ig, or control-Ig fusion proteins in PIPES-Albumin (PIPES-A) buffer containing 25 mM PIPES, 119 mM Cells and transfectants NaCl, 5 mM KCl, and 0.03% human serum albumin (pH 7.4) for 30 min on ice. Cells were then washed in ice-cold PIPES-A and incubated with 5 FLAG-tagged human CD200, HHV-6-CD200, HHV7-CD200, and HHV- ␮g/ml F(abЈ)2 of goat anti-human IgG Fc␥ Ab (Jackson ImmunoResearch 8-CD200 were transfected into Ba/F3 cells using the pMx-neo retrovirus ␣ Laboratories) in PIPES-A for 30 min on ice.
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