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Downloaded From Multiple Products Derived from Two CCL4 Loci: High Incidence of a New Polymorphism in HIV + Patients This information is current as Roger Colobran, Patricia Adreani, Yaqoub Ashhab, Anuska of October 2, 2021. Llano, José A. Esté, Orlando Dominguez, Ricardo Pujol-Borrell and Manel Juan J Immunol 2005; 174:5655-5664; ; doi: 10.4049/jimmunol.174.9.5655 http://www.jimmunol.org/content/174/9/5655 Downloaded from References This article cites 56 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/174/9/5655.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 October 2, 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 Multiple Products Derived from Two CCL4 Loci: High Incidence of a New Polymorphism in HIV؉ Patients1 Roger Colobran,*‡ Patricia Adreani,* Yaqoub Ashhab,* Anuska Llano,† Jose´A. Este´,† Orlando Dominguez,* Ricardo Pujol-Borrell,*‡ and Manel Juan2*‡ Human CCL4/macrophage inflammatory protein (MIP)-1␤ and CCL3/MIP-1␣ are two highly related molecules that belong to a cluster of inflammatory CC chemokines located in chromosome 17. CCL4 and CCL3 were formed by duplication of a common ancestral gene, generating the SCYA4 and SCYA3 genes which, in turn, present a variable number of additional non-allelic copies (SCYA4L and SCYA3L1). In this study, we show that both CCL4 loci (SCYA4 and SCYA4L) are expressed and alternatively generate spliced variants lacking the second exon. In addition, we found that the SCYA4L locus is polymorphic and displays a second allelic variant (hereinafter SCYA4L2) with a nucleotide change in the intron 2 acceptor splice site compared with the one described originally (hereinafter SCYA4L1). Therefore, the pattern of SCYA4L2 transcripts is completely different from that of Downloaded from SCYA4L1, since SCYA4L2 uses several new acceptor splice sites and generates nine new mRNAs. Furthermore, we analyzed the contribution of each locus (SCYA4 and SCYA4L1/L2) to total CCL4 expression in human CD8 T cells by RT-amplified fragment length polymorphism and real-time PCR, and we found that L2 homozygous individuals (L2L2) only express half the levels of CCL4 compared with L1L1 individuals. The analysis of transcripts from the SCYA4L locus showed a lower level in L2 homozygous compared with L1 homozygous individuals (12% vs 52% of total CCL4 transcripts). A possible clinical relevance of these CCL4 when compared (175 ؍ allelic variants was suggested by the higher frequency of the L2 allele in a group of HIV؉ individuals (n http://www.jimmunol.org/ .The Journal of Immunology, 2005, 174: 5655–5664 .((0.00016 ؍ vs 16.6% (p %28.6 ,220 ؍ with controls (n hemokines are a large superfamily of small (ϳ8–15 kDa) important characteristic of cluster chemokines is that they share structurally related molecules that regulate cell traffick- many ligands with few receptors (4). Individual members of the C ing of various types of leukocytes to areas of injury or chemokine superfamily may contribute to this complex relationship infection and play different roles in both inflammatory and homeo- network by two mechanisms of additional variability: 1) pretransla- static processes (1–3). According to the arrangement of a structural tional modifications (such as alternative splicing) (9, 10) and 2) post- cysteine motif found near the NH2 terminus of the mature protein, translational modifications (such as NH2-terminal truncations by 3 chemokines have been divided into four subfamilies: CXC, CC, the dipeptidyl-peptidase (DPP) CD26/DPP IV) (11–14). by guest on October 2, 2021 ␣ CX3C, and C chemokines (4). These chemokines carry out their CCL3/macrophage inflammatory protein (MIP)-1 and CCL4/ biological functions through seven-transmembrane domain G pro- MIP-1␤ are two highly related chemokines that belong to a cluster tein-coupled receptors, which are expressed on several populations of inflammatory CC chemokines located in chromosome 17 (q11- of leukocytes (5–7). To date, 42 chemokines and 18 chemokine q21), which are secreted by specific cells after being triggered by receptors have been identified in humans (8). Ags or mitogenic signals and attract additional cells involved in A remarkable feature of chemokines and chemokine receptors is immune responses (15). These two chemokines, together with their redundancy and binding promiscuity. There are many exam- CCL5/RANTES, are the major HIV-suppressive factors produced ples of a single chemokine binding to several receptors, as well as by CD8ϩ T cells (16) by binding to CCR5, the coreceptor neces- a single chemokine receptor transducing signals for several che- sary for the entry of HIV-R5 strains into CD4ϩ cells (17, 18). mokines. Interestingly, genes encoding the inflammatory chemo- CCL3 and CCL4 were formed by duplication of a common an- kines tend to appear in clusters (human CC subfamily in chromo- cestral gene (15) that originated SCYA3/LD78␣ and SCYA4/ACT-2 some 17 and the CXC subfamily in chromosome 4). Moreover, an genes which in turn have a second non-allelic copy (SCYA3L1/ LD78␤ and SCYA4L/LAG-1) present in variable numbers in the human genome (19). In the case of CCL3, there is a third gene *Laboratory of Immunobiology for Research and Application to Diagnosis, Centre for (SCYA3L2/LD78␥) that is a 5Ј-truncated pseudogene (20). There- Transfusion and Tissue Bank, Institut d’Investigacio´en Cie`ncies de la Salut Germans Trias i Pujol, and †Retrovirology Laboratory, IrsiCaixa Foundation. Hospital Univer- fore, human CCL3 and CCL4 are encoded by two highly related sitari Germans Trias i Pujol, ‡Department of Cell Biology, Physiology and Immu- non-allelic isoforms that have been duplicated and mutated to pro- nology, Universitat Auto`noma de Barcelona, Barcelona, Spain duce two different but highly homologous proteins (Ͼ90% be- Received for publication October 13, 2004. Accepted for publication February tween CCL3 (from SCYA3) and CCL3L1 (from SCYA3L1) pro- 18, 2005. teins, and Ͼ95% between CCL4 (from SCYA4) and CCL4L (from 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 SCYA4L) proteins) (21–23). In CCL3, functional differences have with 18 U.S.C. Section 1734 solely to indicate this fact. been reported between the proteins of two loci. CCL3L1/LD78␤ 1 This work was supported by grants from the Fondo de Investigaciones Sanitarias has been characterized as a more potent CCR5 agonist and a (project FIS 99/1063 and PI 02/0104), the Ministerio de Educacio´n y Ciencia (project greater inhibitor of HIV-1 than CCL3/LD78␣ (24–27). Moreover, BFI 2003–00405), and the Instituto de Salud Carlos III (RC03/03). 2 Address correspondence and reprint requests to Dr. Manel Juan, Laboratory of Im- munobiology for Research and Application to Diagnosis, Immunology Unit, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Barcelona, Spain. 3 Abbreviations used in this paper: DPP, dipeptidyl-peptidase; MIP, macrophage in- E-mail address: [email protected] flammatory protein; GAG, glycosaminoglycan; SDF, stromal cell-derived factor. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 5656 ISO- AND ALLOFORMS OF CCL4 LOCI the higher frequency of the SCYA4L2 allele in a group of HIVϩ individuals when compared with controls. Materials and Methods Isolation and stimulation of human CD8 T cells PBMCs were isolated from total blood by centrifugation over Lymphoprep (Axis-Shield). CD8 T cells were positively selected using magnetic beads coated with mAbs against CD8 (MACS MicroBeads; Miltenyi Biotec) ac- FIGURE 1. Two canonical products of CCL4 and their variants lacking cording to the manufacturer’s instructions. Purity of CD8 T cells was rou- exon 2. cDNA from stimulated CD8 T cells was amplified using primers in tinely Ͼ98%, as determined by flow cytometry. exons 1 and 3. The PCR product was not digested (ND) or digested (D) CCL4 production by purified CD8 T cells was measured at baseline and with MspI. The highest m.w. amplimer in lane ND contains CCL4L and after PHA stimulation (31). Cells were cultured in RPMI 1640 complete CCL4 products resolved after MspI restriction analysis (lane D). The low- medium (Invitrogen Life Technologies) containing 10% FCS, streptomy- ϫ 6 est m.w. amplimer in lane ND contains CCL4L⌬2 and CCL4⌬2 products cin, and penicillin at a cell concentration of 1 10 cells/ml in 24-well plates (Corning Costar). To induce CCL4 production, we added 1 ␮g/ml resolved after MspI digestion (lane D). PHA and 10 ng/ml recombinant human IL-2 (R&D Systems). Cells were harvested and total RNA was extracted after 0, 6, 24, and 48 h of PHA stimulation. Two replicate experiments were performed for each condition. the potent antiviral activity of CCL3L1/LD78␤ is increased due to Human CCL4 amplification the cleavage by CD26/DPP IV, a dipeptidyl-peptidase that cuts CCL4 was amplified by RT-PCR. RNA was extracted using the RNAque- dipeptides from the NH terminus of regulatory peptides with a Downloaded from 2 ous-96 kit (Ambion) and was then retrotranscribed with oligo(dT)15 and proline or alanine residue in the penultimate position (14, 28).
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