{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:01:19Z","timestamp":1791295279456,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2011,4,1]],"date-time":"2011-04-01T00:00:00Z","timestamp":1301616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5+ B lymphocytes from CLL patients and in E1A-cd5\u2013transfected or E1B-cd5\u2013transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5+ but not in CD5\u2212 B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.<\/jats:p>","DOI":"10.4049\/jimmunol.1003050","type":"journal-article","created":{"date-parts":[[2011,3,14]],"date-time":"2011-03-14T04:01:37Z","timestamp":1300075297000},"page":"4835-4844","source":"Crossref","is-referenced-by-count":78,"title":["CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation"],"prefix":"10.1093","volume":"186","author":[{"given":"Soizic","family":"Garaud","sequence":"first","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahsen","family":"Morva","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Lemoine","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hillion","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bordron","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]},{"name":"Department of Oncology, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques-Olivier","family":"Pers","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]},{"name":"Laboratory of Immunology, Brest University Medical School Hospital , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Berthou","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]},{"name":"Department of Oncology, European University of Brittany , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizgar A","family":"Mageed","sequence":"additional","affiliation":[{"name":"Barts and the London Queen Mary, School of Medicine and Dentistry , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Renaudineau","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]},{"name":"Laboratory of Immunology, Brest University Medical School Hospital , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Youinou","sequence":"additional","affiliation":[{"name":"EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany , F29609 Brest ,","place":["France"]},{"name":"Laboratory of Immunology, Brest University Medical School Hospital , F29609 Brest ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,4,15]]},"reference":[{"key":"2025032411205101100_r1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"2025032411205101100_r2","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1172\/JCI23409","article-title":"In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells","volume":"115","author":"Messmer","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2025032411205101100_r3","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1182\/blood-2006-05-021683","article-title":"Differential Noxa\/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity","volume":"109","author":"Smit","year":"2007","journal-title":"Blood"},{"key":"2025032411205101100_r4","doi-asserted-by":"crossref","first-page":"4537","DOI":"10.1182\/blood-2002-05-1525","article-title":"Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production","volume":"100","author":"Gary-Gouy","year":"2002","journal-title":"Blood"},{"key":"2025032411205101100_r5","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1182\/blood-2005-02-0597","article-title":"An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes","volume":"106","author":"Renaudineau","year":"2005","journal-title":"Blood"},{"key":"2025032411205101100_r6","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/sj.gene.6364253","article-title":"Characterization of the human CD5 endogenous retrovirus-E in B lymphocytes","volume":"6","author":"Renaudineau","year":"2005","journal-title":"Genes Immun."},{"key":"2025032411205101100_r7","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.4049\/jimmunol.181.3.2010","article-title":"Selection of the alternative exon 1 from the cd5 gene down-regulates membrane level of the protein in B lymphocytes","volume":"181","author":"Garaud","year":"2008","journal-title":"J. Immunol."},{"key":"2025032411205101100_r8","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1749-6632.2009.04616.x","article-title":"IL-10 production by B cells expressing CD5 with the alternative exon 1B","volume":"1173","author":"Garaud","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2025032411205101100_r9","doi-asserted-by":"crossref","first-page":"4146","DOI":"10.1182\/blood.V89.11.4146","article-title":"Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells","volume":"89","author":"Jurlander","year":"1997","journal-title":"Blood"},{"key":"2025032411205101100_r10","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.4049\/jimmunol.179.7.4335","article-title":"Natural phosphorylation of CD5 in chronic lymphocytic leukemia B cells and analysis of CD5-regulated genes in a B cell line suggest a role for CD5 in malignant phenotype","volume":"179","author":"Gary-Gouy","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411205101100_r11","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1146\/annurev.immunol.19.1.683","article-title":"Interleukin-10 and the interleukin-10 receptor","volume":"19","author":"Moore","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411205101100_r12","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1006\/meth.1996.0393","article-title":"B-cell\u2013derived IL-10: production and function","volume":"11","author":"Burdin","year":"1997","journal-title":"Methods"},{"key":"2025032411205101100_r13","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.4049\/jimmunol.0802412","article-title":"IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation","volume":"182","author":"Garaud","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411205101100_r14","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/82717","article-title":"Reciprocal regulation of polarized cytokine production by effector B and T cells","volume":"1","author":"Harris","year":"2000","journal-title":"Nat. Immunol."},{"key":"2025032411205101100_r15","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1084\/jem.181.3.839","article-title":"Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus","volume":"181","author":"Llorente","year":"1995","journal-title":"J. Exp. Med."},{"key":"2025032411205101100_r16","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1084\/jem.175.3.671","article-title":"Interleukin 10 and transforming growth factor \u03b2 cooperate to induce anti\u2013CD40-activated naive human B cells to secrete immunoglobulin A","volume":"175","author":"Defrance","year":"1992","journal-title":"J. Exp. Med."},{"key":"2025032411205101100_r17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0925-5710(95)00395-9","article-title":"The role of interleukin-10 (IL-10) in chronic B-lymphocytic leukemia: IL-10 prevents leukemic cells from apoptotic cell death","volume":"62","author":"Kitabayashi","year":"1995","journal-title":"Int. J. Hematol."},{"key":"2025032411205101100_r18","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1182\/blood.V97.1.256","article-title":"Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome","volume":"97","author":"Fayad","year":"2001","journal-title":"Blood"},{"key":"2025032411205101100_r19","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.4049\/jimmunol.178.5.2623","article-title":"The JAK-STAT signaling pathway: input and output integration","volume":"178","author":"Murray","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411205101100_r20","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: regulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411205101100_r21","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1182\/blood-2007-04-087734","article-title":"Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas","volume":"111","author":"Ding","year":"2008","journal-title":"Blood"},{"key":"2025032411205101100_r22","doi-asserted-by":"crossref","first-page":"20653","DOI":"10.1074\/jbc.270.35.20653","article-title":"Phosphorylation of the transcription factor NFATp inhibits its DNA binding activity in cyclosporin A-treated human B and T cells","volume":"270","author":"Park","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2025032411205101100_r23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3109\/10428199409052666","article-title":"The value of scoring systems for the diagnosis of biphenotypic leukemia and mature B-cell disorders","volume":"13","author":"Matutes","year":"1994","journal-title":"Leuk. Lymphoma"},{"key":"2025032411205101100_r24","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V","article-title":"A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis","volume":"48","author":"Binet","year":"1981","journal-title":"Cancer"},{"key":"2025032411205101100_r25","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1182\/blood.V99.3.1023","article-title":"CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease","volume":"99","author":"Hamblin","year":"2002","journal-title":"Blood"},{"key":"2025032411205101100_r26","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1182\/blood.V60.6.1305.1305","article-title":"Two new acute lymphoblastic leukemia cell lines with early B-cell phenotypes","volume":"60","author":"Findley","year":"1982","journal-title":"Blood"},{"key":"2025032411205101100_r27","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative polymerase chain reaction and the 2\u2212\u0394\u0394C(T) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2025032411205101100_r28","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1172\/JCI119869","article-title":"B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues","volume":"100","author":"Frank","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2025032411205101100_r29","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.molimm.2008.07.037","article-title":"A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells","volume":"46","author":"Lee","year":"2009","journal-title":"Mol. Immunol."},{"key":"2025032411205101100_r30","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1365-2141.2010.08249.x","article-title":"JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation","volume":"150","author":"Oku","year":"2010","journal-title":"Br. J. Haematol."},{"key":"2025032411205101100_r31","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/S1357-2725(99)00069-2","article-title":"Role of nuclear factor of activated T cells (NFAT) in the expression of interleukin-5 and other cytokines involved in the regulation of hemopoetic cells","volume":"31","author":"De Boer","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2025032411205101100_r32","doi-asserted-by":"crossref","first-page":"36210","DOI":"10.1074\/jbc.M406354200","article-title":"Role of NFAT proteins in IL13 gene transcription in mast cells","volume":"279","author":"Monticelli","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025032411205101100_r33","first-page":"1557","article-title":"Leukemia-associated changes identified by quantitative flow cytometry. II. CD5 over-expression and monitoring in B-CLL","volume":"8","author":"Lavabre-Bertrand","year":"1994","journal-title":"Leukemia"},{"key":"2025032411205101100_r34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/sj.gene.6363773","article-title":"Cell cycle effects of IL-10 on malignant B-1 cells","volume":"2","author":"Yen Chong","year":"2001","journal-title":"Genes Immun."},{"key":"2025032411205101100_r35","first-page":"6","article-title":"RNA interference of IL-10 in leukemic B-1 cells","volume":"4","author":"McCarthy","year":"2004","journal-title":"Cancer Immun."},{"key":"2025032411205101100_r36","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1084\/jem.185.6.1035","article-title":"Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes","volume":"185","author":"Karras","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025032411205101100_r37","doi-asserted-by":"crossref","first-page":"7736","DOI":"10.1158\/0008-5472.CAN-08-1125","article-title":"Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation","volume":"68","author":"Qin","year":"2008","journal-title":"Cancer Res."},{"key":"2025032411205101100_r38","doi-asserted-by":"crossref","first-page":"4779","DOI":"10.4049\/jimmunol.178.8.4779","article-title":"IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3","volume":"178","author":"Staples","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411205101100_r39","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3109\/10428199609054868","article-title":"Nuclear NF-ATp is a hallmark of unstimulated B cells from B-CLL patients","volume":"23","author":"Schuh","year":"1996","journal-title":"Leuk. Lymphoma"},{"key":"2025032411205101100_r40","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1182\/blood-2009-10-230060","article-title":"STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells","volume":"115","author":"Hazan-Halevy","year":"2010","journal-title":"Blood"},{"key":"2025032411205101100_r41","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1002\/1521-4141(2002010)32:10<2971::AID-IMMU2971>3.0.CO;2-G","article-title":"NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription","volume":"32","author":"Monticelli","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"2025032411205101100_r42","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.4049\/jimmunol.165.3.1612","article-title":"Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression","volume":"165","author":"Benkhart","year":"2000","journal-title":"J. Immunol."},{"key":"2025032411205101100_r43","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1016\/j.molimm.2008.02.020","article-title":"Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene","volume":"45","author":"Unterberger","year":"2008","journal-title":"Mol. Immunol."},{"key":"2025032411205101100_r44","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1002\/eji.1830220314","article-title":"Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10","volume":"22","author":"O\u2019Garra","year":"1992","journal-title":"Eur. J. Immunol."},{"key":"2025032411205101100_r45","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.immuni.2008.03.017","article-title":"A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses","volume":"28","author":"Yanaba","year":"2008","journal-title":"Immunity"},{"key":"2025032411205101100_r46","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1084\/jem.175.5.1213","article-title":"Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells","volume":"175","author":"Ishida","year":"1992","journal-title":"J. Exp. Med."},{"key":"2025032411205101100_r47","first-page":"178","article-title":"Role of IL-10 in the distribution of B cell subsets in the mouse B-1 cell population","volume":"14","author":"Pers","year":"2003","journal-title":"Eur. Cytokine Netw."},{"key":"2025032411205101100_r48","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1182\/blood-2007-09-111344","article-title":"Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy","volume":"112","author":"Muzio","year":"2008","journal-title":"Blood"},{"key":"2025032411205101100_r49","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/sj.leu.2402327","article-title":"CD5-induced apoptosis of B cells in some patients with chronic lymphocytic leukemia","volume":"16","author":"Pers","year":"2002","journal-title":"Leukemia"},{"key":"2025032411205101100_r50","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S1074-7613(00)80188-0","article-title":"Manipulating immune responses with immunosuppressive agents that target NFAT","volume":"12","author":"Kiani","year":"2000","journal-title":"Immunity"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/8\/4835\/61695752\/1003050.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/8\/4835\/61695752\/1003050.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T14:46:40Z","timestamp":1743173200000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/186\/8\/4835\/7990096"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,4]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2011,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1003050","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,4]]},"published":{"date-parts":[[2011,4]]}}}