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Regulatory Activity T Lymphocytes with + Function in CD4 Chemokine Chemokine Receptor Expression and Function in CD4 + T Lymphocytes with Regulatory Activity This information is current as Silvia Sebastiani, Paola Allavena, Cristina Albanesi, of September 24, 2021. Francesca Nasorri, Giancarlo Bianchi, Claudia Traidl, Silvano Sozzani, Giampiero Girolomoni and Andrea Cavani J Immunol 2001; 166:996-1002; ; doi: 10.4049/jimmunol.166.2.996 http://www.jimmunol.org/content/166/2/996 Downloaded from References This article cites 37 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/166/2/996.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 24, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Chemokine Receptor Expression and Function in CD4؉ T Lymphocytes with Regulatory Activity1 Silvia Sebastiani,* Paola Allavena,† Cristina Albanesi,* Francesca Nasorri,* Giancarlo Bianchi,† Claudia Traidl,* Silvano Sozzani,† Giampiero Girolomoni,* and Andrea Cavani2* We have investigated the chemokine receptor expression and migratory behavior of a new subset of nickel-specific skin-homing regulatory CD4؉ T cells (ThIL-10) releasing high levels of IL-10, low IFN-␥, and undetectable IL-4. These cells inhibit in a IL-10-dependent manner the capacity of dendritic cells to activate nickel-specific Tc1 and Th1 lymphocytes. RNase protection assay and FACS analysis revealed the expression of a vast repertoire of chemokine receptors on resting ThIL-10, including the Th1-associated CXCR3 and CCR5, and the Th2-associated CCR3, CCR4, and CCR8, the latter at higher levels compared with Th2 cells. The most active chemokines for resting ThIL-10, in terms of calcium mobilization and in vitro migration, were in order of potency: CCL2 (monocyte chemoattractant protein-1, CCR2 ligand), CCL4 (macrophage-inflammatory protein-1␤, CCR5 Downloaded from ligand), CCL3 (macrophage-inflammatory protein-1␣, CCR1/5 ligand), CCL17 (thymus and activation-regulated chemokine, CCR4 ligand), CCL1 (I-309, CCR8 ligand), CXCL12 (stromal-derived factor-1, CXCR4), and CCL11 (eotaxin, CCR3 ligand). Consistent with receptor expression down-regulation, activated ThIL-10 exhibited a reduced or absent response to most chemo- kines, but retained a significant migratory capacity to I-309, monocyte chemoattractant protein-1, and thymus and activation- regulated chemokine. I-309, which was ineffective on Th1 lymphocytes, attracted more efficiently ThIL-10 than Th2 cells. I-309 and CCR8 mRNAs were not detected in unaffected skin and were up-regulated at the skin site of nickel-allergic reaction, with an http://www.jimmunol.org/ earlier expression kinetics compared with IL-10 and IL-4. Results indicate that skin-homing regulatory ThIL-10 lymphocytes coexpress functional Th1- and Th2-associated chemokine receptors, and that CCR8/I-309-driven recruitment of both resting and activated ThIL-10 cells may be critically involved in the regulation of Th1-mediated skin allergic disorders. The Journal of Immunology, 2001, 166: 996–1002. ompelling evidence indicates the existence of specialized cutaneous lymphocyte-associated Ag (CLA), and block in a IL- CD4ϩ T lymphocytes with the potential to regulate a 10-dependent manner the differentiation and maturation of den- variety of immune responses through the release of sup- dritic cells, thus impairing their capacity to activate nickel-specific C ϩ by guest on September 24, 2021 pressive cytokines (1–3). In particular, IL-10-producing CD4 T Tc1 and Th1 effector lymphocytes (12). cells appear to be profoundly involved in the modulation of auto- Many recent findings indicate that chemokine receptors are dif- immune diseases as well as in the induction of transplantation ferentially expressed on memory T cells depending on their po- tolerance (4–6). Allergic diseases are the consequence of exag- larization (13–18), with Th1 lymphocytes expressing CCR5 and gerated immune responses against innocuous non-self Ags. Aller- CXCR3, and Th2 lymphocytes CCR3, CCR4, and CCR8. As a gic contact dermatitis to nickel is a prototypic type 1-mediated consequence, selective chemotactic stimuli contribute to the dif- immune response and depends upon the recruitment of Th1 and ferential positioning of Th1 and Th2 cells within tissues (19–21). Tc1 lymphocytes at the skin site of nickel application in sensitized Here, we analyzed the chemokine receptor profile and migratory individuals (7–10). We have recently found that the skin and pe- properties of skin-homing nickel-specific ThIL-10 lymphocytes. ripheral blood of nickel-allergic patients as well as the blood of Our results demonstrate that resting ThIL-10 cells coexpress func- healthy donors bear a substantial proportion of nickel-specific tional Th1 and Th2 chemokine receptors and migrate in response CD4ϩ T clones which produce high amounts of IL-10, low or to a variety of chemokines. Upon activation, ThIL-10 cells are at- undetectable IFN-␥, and no IL-4 (11). These nickel-specific IL- tracted exclusively by CCL1 (I-309), CCL2 (monocyte chemoat- 10-producing Th cells (ThIL-10)3 express the skin-homing receptor, tractant protein-1, MCP-1), CCL17 (thymus and activation-regu- lated chemokine, TARC), and CXCL12 (stromal derived factor 1, SDF-1). I-309, which is produced in the skin affected with allergic *Laboratory of Immunology, Istituto Dermopatico dell’Immacolata, IRCCS, Rome, IL-10 Italy; and †Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy contact dermatitis to nickel, attracts Th and Th2, but not Th1 cells, and may thus contribute to the regulation of the Th1-medi- Received for publication July 27, 2000. Accepted for publication October 30, 2000. ated skin inflammation. 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 with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods 1 This work was supported by the European Community (Biomed 2 Program, Grant BMH4-CT98h3713), the Istituto Superiore di Sanita`(AIDS Project, Grant 40B/1.18), Culture medium and Abs the Associazione Italiana per la Ricerca sul Cancro, and the Ministero della Sanita`. T lymphocytes were cultured in RPMI 1640 supplemented with 2 mM 2 Address correspondence and reprint requests to Dr. Andrea Cavani, Laboratory of glutamine, 1 mM sodium pyruvate, 1% nonessential amino acids, 0.05 mM Immunology, Istituto Dermopatico dell’Immacolata, IRCCS Via Monti di Creta 104, 2-ME, 100 U/ml penicillin, and 100 ␮g/ml streptomycin (all from Life I-00167 Rome, Italy. E-mail address: [email protected] 3 Abbreviations used in this paper: ThIL-10, IL-10-producing Th cells; CLA, cutane- ous lymphocyte-associated Ag; MCP, monocyte chemoattractant protein; TARC, thy- rophage-inflammatory protein; IP-10, IFN-induced protein of 10 kDa; Tr1, T mus and activation-regulated chemokine; SDF, stromal-derived factor; MIP, mac- regulatory cell 1. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 997 ϩ Technologies, Chagrin Falls, OH) (complete RPMI) plus 10% heat-inac- Intracellular Ca2 concentration measurements tivated FCS (HyClone Logan, UT) or 5% autologous plasma. The anti- CD28 mAb (Leu-28, IgG1) was purchased from Becton Dickinson (San T cell clones were either left untreated or activated with anti-CD3 plus ϫ Jose, Ca). Mouse mAbs anti-human CCR1 (53504.111, IgG2 ), CCR2 anti-CD28 for 48 h in the presence of 30 U/ml IL-2. Thereafter, cells (5 B 6 ␮ (48607.121, IgG2 ), CCR5 (45531.111, IgG2 ), and CXCR3 (49801.111, 10 /ml) were washed and loaded with 8 M Fluo-3/acetoxymethyl ester in B B ␮ IgG1) were obtained from R&D Systems (Minneapolis, MN); anti-CCR3 the presence of 1 M pluronic F-127 (Molecular Probes, Eugene, OR) in complete RPMI with 1% FBS for 40 min at 37°C with frequent gentle (LS63 7B11, IgG2A) and anti-CCR4 (328B, IgG) mAbs were kindly pro- vided by Leukosite (Cambridge, MA) and ICOS (Bothell, WA), respec- agitation. Cells were then washed twice, stimulated with CCL3 (macro- ␣ tively; anti-CXCR1 (5A12, IgG2 ), CXCR2 (6C6, IgG1) and CXCR4 phage inflammatory protein (MIP)-1 , 200 ng/ml), MCP-1 (200 ng/ml), B ␤ (12G5, IgG2 ) were purchased from PharMingen (San Diego, CA). Anti- CCL11 (eotaxin, 400 ng/ml), TARC (100 ng/ml), CCL4 (MIP-1 , 100 A ␤ CD3 (UCHT-1, IgG1) was obtained from Immunotech (Marseille, France); ng/ml), CCL19 (MIP-3 , 30 ng/ml), I-309 (200 ng/ml), CXCL8 (IL-8, 100 the FITC-conjugated anti-CLA mAb (HECA-452, rat IgM), the control ng/ml), CXCL10 (IFN-induced protein of 10 kDa (IP-10), 100 ng/ml), and isotype FITC-conjugated rat IgM, and the control mouse IgG were pur- SDF-1 (100 ng/ml) (all from R&D Systems), and finally analyzed on a chased from PharMingen. FITC-conjugated goat anti-mouse IgG were ob- FACScan. Cells and chemokines were maintained at 37°C during the tained from Dako (Glostrup, Denmark). assay. Migration assay T cell clones Chemotactic property of each chemokine was evaluated measuring the ␮ T cell lines were derived from the blood and skin of nonatopic patients lymphocyte migration through a 5- m pore polycarbonate filter in 24-well transwell chambers (Corning Costar, Cambridge MA) as previously de- affected by allergic contact dermatitis to nickel, as previously described IL-10 (12).
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