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CX3CR1 Are Potent HIV Coreceptors Two Novel Fully Functional Two Novel Fully Functional Isoforms of CX3CR1 Are Potent HIV Coreceptors Alexandre Garin, Nadine Tarantino, Sophie Faure, Mehdi Daoudi, Cédric Lécureuil, Anne Bourdais, Patrice Debré, This information is current as Philippe Deterre and Christophe Combadiere of October 2, 2021. J Immunol 2003; 171:5305-5312; ; doi: 10.4049/jimmunol.171.10.5305 http://www.jimmunol.org/content/171/10/5305 Downloaded from References This article cites 49 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/171/10/5305.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 *average by guest on October 2, 2021 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Two Novel Fully Functional Isoforms of CX3CR1 Are Potent HIV Coreceptors1 Alexandre Garin, Nadine Tarantino, Sophie Faure, Mehdi Daoudi, Ce´dric Le´cureuil, Anne Bourdais, Patrice Debre´, Philippe Deterre, and Christophe Combadiere2 We identified two novel isoforms of the human chemokine receptor CX3CR1, produced by alternative splicing and with N- terminal regions extended by 7 and 32 aa. Expression of the messengers coding these isoforms, compared with that of previously described V28 messengers, is lower in monocytes and NK cells, but higher in CD4؉ T lymphocytes. CX3CR1 and its extended isoforms were expressed in HEK-293 cells and compared for expression, ligand binding, and cellular responses. In steady state experiments, all three CX3CR1 isoforms bound CX3CL1 with similar affinity. In kinetic binding studies, however, kon and koff were significantly greater for the extended CX3CR1 isoforms, thereby suggesting that the N-terminal extensions may alter the functions induced by CX3CL1. In signaling studies, all three CX3CR1 isoforms mediated agonist-dependent calcium mobilization, Downloaded from but the EC50 was lower for the extended than for the standard isoforms. In addition, chemotactic responses for these extended isoforms shifted left, also indicating a more sensitive response. Finally, the longer variants appeared to be more potent HIV coreceptors when tested in fusion and infection assays. In conclusion, we identified and characterized functionally two novel isoforms of CX3CR1 that respond more sensitively to CX3CL1 and HIV viral envelopes. These data reveal new complexity in CX3CR1 cell activation and confirm the critical role of the N-terminal domain of the chemokine receptors in ligand recognition and cellular response. The Journal of Immunology, 2003, 171: 5305–5312. http://www.jimmunol.org/ hemokines are involved in diverse physiological and CCR9 isoforms, termed CCR9A and CCR9B, which differ by 12 pathological conditions, mainly through their deploy- aa residues, differ in their ligand-binding affinity, Ca2ϩ flux, and C ment of leukocytes (1–3). They mediate their effects via chemotaxis (17). Similar modifications were observed for CXCR4- specific interactions with extracellular regions of chemokine re- lo, an N-terminal protein isoform of CXCR4 (18). Together these ceptors expressed at the leukocyte cell surface. The N-terminal data suggest that N-terminal isoforms of chemokine receptors can domain of these receptors has been described as a crucial deter- alter biochemical functions. Post-transcriptional modifications in minant in ligand binding and signaling (4–7), and thus alterations the carboxyl-terminal regions have also been reported to affect the by guest on October 2, 2021 in this domain may be of critical importance. Furthermore, the regulation of chemokine receptor functions (19). N-terminal domain plays a key role in interacting with the HIV We previously reported allelic isoforms of CX3CR1 associated envelope gp120 (8–10), at least for CCR5 and CXCR4, the two with rapid HIV disease progression (20) and reduced susceptibility principal HIV coreceptors (11–13). Abs raised against the N ter- to acute coronary events (21). CX3CR1 is the receptor for minals of CXCR4 and CCR5 inhibit cell fusion and infection with CX3CL1, the only member of the CX3C subfamily (22). CX3CR1 HIV-1 (8, 14), and the first 20 N-terminal residues of CCR5 func- is preferentially expressed in monocytes and NK cells (23) as well tion as a coreceptor when grafted onto a CCR2 backbone (15, 16). ϩ as in CD8 T cells (24), glial cells and astrocytes (25) and may A current model of chemokine binding suggests a two-step mech- directly modulate neuronal activity and survival (26, 27). CX3CL1 anism involving initial recognition of the chemokine receptor N- and the chemokine CXCL16 (28) exist in both soluble and mem- terminal domain, followed by more specific interactions with the other extracellular domains. Recent findings of post-transcriptional brane-anchored forms. The soluble form of CX3CL1 recruits lym- modifications in the N-terminal domain of chemokine receptors phocytes and monocytes (22, 29), whereas membrane-bound indicate that regulation of receptor function is still more complex. CX3CL1 directly mediates the capture and firm adhesion of CX3CR1-expressing leukocytes (23, 30); this discovery revealed a novel pathway for leukocyte activation. Recent reports point out physiopathological correlates to these functions: CX3CL1 knock- Laboratoire d’Immunologie Cellulaire et Tissulaire, Institut National de la Sante´etde out mice are less susceptible than their wild-type littermates to la Recherche Me´dicale, Unite´543, Hoˆpital Pitie´-Salpeˆtriere, Paris, France cerebral ischemia-reperfusion injury (31), while CX3CR1 KO Received for publication October 25, 2002. Accepted for publication September 16, 2003. mice reject cardiac transplants more slowly in the presence of cy- The costs of publication of this article were defrayed in part by the payment of page closporine (32) and form fewer atherosclerotic lesions in an apo- charges. This article must therefore be hereby marked advertisement in accordance lipoprotein E background (33, 34). CX3CR1 plays a role in yet with 18 U.S.C. Section 1734 solely to indicate this fact. another disease; like CCR5 and CXCR4, it serves as an HIV co- 1 This work was supported by a grant from the Agence National de Recherche sur le receptor (35, 36). CX3CL1 specifically blocks CX3CR1 interaction SIDA and an Action Concertée Incitative grant for Jeunes Chercheurs from the French Ministry of Research. A.G. and S.F. are fellows of the Agence National de with the HIV envelope gp120 (37). The physiological relevance of Recherche sur le SIDA, and M.D. is a fellow of the Ministry of Research. CX3CR1 in HIV nonetheless remains unclear (20, 38, 39). 2 Address correspondence and reprint requests to Dr. Christophe Combadiere, Labo- Here we identify and functionally characterize two novel ratoire d’Immunologie Cellulaire et Tissulaire, Institut National de la Sante´etdela Recherche Me´dicale, Unite´543, Hoˆpital Pitie´-Salpeˆtriere, 91 boulevard de l’Hoˆpital, CX3CR1 isoforms that differ from the classic form of CX3CR1 (re- AP-HP, 75634 Paris Cedex 13, France. E-mail address: [email protected] ferred to here as Met ϩ1) by N-terminal additions of 7 and 32 aa. Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 5306 CHARACTERIZATION OF CX3CR1 ISOFORMS Materials and Methods Generation of specific Met Ϫ32 isoform polyclonal Abs Cells and culture conditions Rabbit polyclonal Abs were raised against the human Met Ϫ7 and Met Ϫ32 CX3CR1 isoforms (AGRO-BIO, La Ferte´ Saint Aubin, France) and Resting PBMCs of heparinized venous blood taken from healthy volun- further purified. teers were isolated by a one-step centrifugation on a Ficoll separating so- ϩ ϩ lution (Biochrom, Berlin, Germany). CD4 T lymphocytes, CD8 T lym- Western blot analysis of CX3CR1 protein phocytes, and NK cells were then isolated by positive selection through the use, respectively, of anti-CD4 mAbs, anti-CD8 mAbs, and a mixture of HEK-293 cells were suspended at 108 cells/ml in 20 mM Tris (pH 7.5), 1 anti-CD16 and anti-CD56 mAbs coupled with magnetic beads (Miltenyi mM EDTA, and 1 mM DTT supplemented with complete protease inhib- Biotec, Paris, France). Negative selection, using a mixture of anti-CD2, itor cocktail (Roche, Meylan, France). The cells were then homogenized at -CD7, -CD16, -CD19, and -CD56 mAbs coupled with magnetic beads 4°C in a Dounce homogenizer (Kontes, Vineland, NJ). Nuclear and cellular (Dynal, Compiegne, France), was used to enrich monocytes. Flow cyto- debris was removed by centrifugation for 10 min at 10,000 ϫ g. The metric analysis confirmed that the enriched cell populations were 95% supernatant was then centrifuged at 100,000 ϫ g at 4°C for 30 min. The pure. U373MG-CD4, HeLa, and HEK-293 cell lines were maintained in pellet was suspended in lysis buffer (20 mM Tris, 140 mM NaCl, 1 mM DMEM (Life Technologies SARL, Cergy Pontoise, France), supplemented EDTA, and 0.1% Nonidet P-40, pH 7.4) supplemented with complete pro- with 10% FCS, 1 mM L-glutamine, and penicillin-streptomycin (100 tease inhibitor cocktail. The samples were then assayed for protein content U/ml). Cells used for HIV fusion and infection were provided by Dr. M. and resuspended in sample buffer (50 mM Tris (pH 7), 3% SDS, 10% Alizon (Institut National de la Santé et de la Recherche Médicale, Unité glycerol, 5% 2-ME, and bromophenol blue). Proteins were separated by 567, Universite Paris V-Rene Descartes, Paris, France).
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