{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:56:12Z","timestamp":1791064572345,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2010,9,1]],"date-time":"2010-09-01T00:00:00Z","timestamp":1283299200000},"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":[[2010,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We recently showed that mice lacking B and T lymphocyte attenuator (BTLA), a third inhibitory coreceptor expressed on B cells and T cells, exhibit an increased Ag-specific IgG response and gradually develop hyper-\u03b3\u2013globulinemia and autoantibody production. Recent studies revealed that follicular Th (Tfh) cells, which are non-Th1, non-Th2 effector T cells that express CXCR5 and provide help for B cells to produce Ig, also express BTLA. However, the role of BTLA in Tfh cell function remains unknown. In this study, we examined the regulatory role of BTLA in the development and function of Tfh cells. We found that CXCR5+ Tfh cells expressed higher levels of BTLA than did CXCR5\u2212 conventional CD4+ T cells. We also found that adoptive transfer of BTLA\u2212\/\u2212 CD4+ T cells, stimulated under Tfh cell-inducing conditions (Tfh-like cells), to wild-type (WT) mice induced more Ag-specific IgG2a and IgG2b production compared with that of WT Tfh-like cells. By contrast, another adoptive-transfer experiment using BTLA\u2212\/\u2212 mice as recipients showed that the expression of BTLA on B cells was not involved in the regulation of Tfh-like cell-mediated Ag-specific IgG responses. Moreover, the development of IL-21\u2013producing CXCR5+ Tfh-like cells was significantly increased in BTLA\u2212\/\u2212 CD4+ T cells compared with WT CD4+ T cells. Furthermore, Tfh-like cell-mediated IgG responses were abolished when IL-21R\u2212\/\u2212 mice were used as recipients. These results suggest that BTLA signaling suppresses IL-21 production from Tfh cells and subsequent Tfh cell-mediated IgG responses.<\/jats:p>","DOI":"10.4049\/jimmunol.0903839","type":"journal-article","created":{"date-parts":[[2010,7,26]],"date-time":"2010-07-26T20:59:40Z","timestamp":1280177980000},"page":"2730-2736","source":"Crossref","is-referenced-by-count":67,"title":["B and T Lymphocyte Attenuator Suppresses IL-21 Production from Follicular Th Cells and Subsequent Humoral Immune Responses"],"prefix":"10.1093","volume":"185","author":[{"given":"Daisuke","family":"Kashiwakuma","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]},{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Suto","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]},{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Hiramatsu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]},{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Takatori","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichiro","family":"Kagami","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]},{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Hirose","sequence":"additional","affiliation":[{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihiko","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itsuo","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Research Center for Allergy and Clinical Immunology, Asahi General Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Graduate School of Medicine, Chiba University , Asahi, Chiba ,","place":["Japan"]},{"name":"Department of Allergy and Clinical Immunology, Chiba University Hospital , Asahi, Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,9,1]]},"reference":[{"key":"2025032411495388100_r1","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nri1714","article-title":"Follicular B helper T cells in antibody responses and autoimmunity","volume":"5","author":"Vinuesa","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411495388100_r2","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1146\/annurev.immunol.26.021607.090344","article-title":"T follicular helper (TFH) cells in normal and dysregulated immune responses","volume":"26","author":"King","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411495388100_r3","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.immuni.2009.03.003","article-title":"Follicular helper T cells: lineage and location","volume":"30","author":"Fazilleau","year":"2009","journal-title":"Immunity"},{"key":"2025032411495388100_r4","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.4049\/jimmunol.166.6.3659","article-title":"Cutting edge: critical role of inducible costimulator in germinal center reactions","volume":"166","author":"Dong","year":"2001","journal-title":"J. Immunol."},{"key":"2025032411495388100_r5","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/ni947","article-title":"Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses","volume":"4","author":"Mak","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032411495388100_r6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/35040504","article-title":"Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function","volume":"408","author":"Parrish-Novak","year":"2000","journal-title":"Nature"},{"key":"2025032411495388100_r7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev.immunol.26.021607.090316","article-title":"Interleukin-21: basic biology and implications for cancer and autoimmunity","volume":"26","author":"Spolski","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411495388100_r8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cytogfr.2009.02.002","article-title":"Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease","volume":"20","author":"Monteleone","year":"2009","journal-title":"Cytokine Growth Factor Rev."},{"key":"2025032411495388100_r9","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity"},{"key":"2025032411495388100_r10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.immuni.2008.06.001","article-title":"A fundamental role for interleukin-21 in the generation of T follicular helper cells","volume":"29","author":"Vogelzang","year":"2008","journal-title":"Immunity"},{"key":"2025032411495388100_r11","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1182\/blood-2002-04-1115","article-title":"Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(\u03b5) transcription of IL-4-stimulated B cells","volume":"100","author":"Suto","year":"2002","journal-title":"Blood"},{"key":"2025032411495388100_r12","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1126\/science.1077002","article-title":"A critical role for IL-21 in regulating immunoglobulin production","volume":"298","author":"Ozaki","year":"2002","journal-title":"Science"},{"key":"2025032411495388100_r13","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1084\/jem.20062206","article-title":"IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses","volume":"203","author":"Harada","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025032411495388100_r14","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.it.2005.03.010","article-title":"The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA","volume":"26","author":"Croft","year":"2005","journal-title":"Trends Immunol."},{"key":"2025032411495388100_r15","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nri1917","article-title":"Balancing co-stimulation and inhibition with BTLA and HVEM","volume":"6","author":"Murphy","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411495388100_r16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1600-065X.2009.00783.x","article-title":"The CD160, BTLA, LIGHT\/HVEM pathway: a bidirectional switch regulating T-cell activation","volume":"229","author":"Cai","year":"2009","journal-title":"Immunol. Rev."},{"key":"2025032411495388100_r17","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0092-8674(00)81363-X","article-title":"Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF\/NGF receptor family","volume":"87","author":"Montgomery","year":"1996","journal-title":"Cell"},{"key":"2025032411495388100_r18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/ni1144","article-title":"B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator","volume":"6","author":"Sedy","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032411495388100_r19","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1073\/pnas.0409071102","article-title":"A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator","volume":"102","author":"Gonzalez","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411495388100_r20","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ni944","article-title":"BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1","volume":"4","author":"Watanabe","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032411495388100_r21","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1002\/art.23674","article-title":"Development of autoimmune hepatitis-like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator","volume":"58","author":"Oya","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025032411495388100_r22","doi-asserted-by":"crossref","first-page":"7837","DOI":"10.4049\/jimmunol.175.12.7837","article-title":"Identification of T cell-restricted genes, and signatures for different T cell responses, using a comprehensive collection of microarray datasets","volume":"175","author":"Chtanova","year":"2005","journal-title":"J. Immunol."},{"key":"2025032411495388100_r23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S1074-7613(02)00295-9","article-title":"IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity","volume":"16","author":"Kasaian","year":"2002","journal-title":"Immunity"},{"key":"2025032411495388100_r24","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1126\/science.2125367","article-title":"Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo","volume":"250","author":"Murphy","year":"1990","journal-title":"Science"},{"key":"2025032411495388100_r25","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1084\/jem.20072057","article-title":"Development and characterization of IL-21-producing CD4+ T cells","volume":"205","author":"Suto","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032411495388100_r26","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1182\/blood.V95.4.1370.004k29_1370_1377","article-title":"Both stat5a and stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue","volume":"95","author":"Kagami","year":"2000","journal-title":"Blood"},{"key":"2025032411495388100_r27","doi-asserted-by":"crossref","first-page":"7286","DOI":"10.4049\/jimmunol.0902490","article-title":"T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment","volume":"183","author":"Cheung","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411495388100_r28","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.coi.2009.05.010","article-title":"Follicular helper T cells as cognate regulators of B cell immunity","volume":"21","author":"McHeyzer-Williams","year":"2009","journal-title":"Curr. Opin. Immunol."},{"key":"2025032411495388100_r29","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.4049\/jimmunol.172.10.5931","article-title":"An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection","volume":"172","author":"Han","year":"2004","journal-title":"J. Immunol."},{"key":"2025032411495388100_r30","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.4049\/jimmunol.182.3.1509","article-title":"B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK","volume":"182","author":"Vendel","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411495388100_r31","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1073\/pnas.0409512102","article-title":"NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression","volume":"102","author":"Mehta","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411495388100_r32","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S1074-7613(00)80073-4","article-title":"The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines","volume":"10","author":"Kim","year":"1999","journal-title":"Immunity"},{"key":"2025032411495388100_r33","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/ni.1690","article-title":"The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells","volume":"10","author":"Bauquet","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025032411495388100_r34","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1189\/jlb.0909639","article-title":"c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-\u03b2 inhibits c-Maf-induced IL-21 production in CD4+ T cells","volume":"87","author":"Hiramatsu","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2025032411495388100_r35","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science"},{"key":"2025032411495388100_r36","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation","volume":"325","author":"Johnston","year":"2009","journal-title":"Science"},{"key":"2025032411495388100_r37","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.immuni.2009.07.002","article-title":"The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment","volume":"31","author":"Yu","year":"2009","journal-title":"Immunity"},{"key":"2025032411495388100_r38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1084\/jem.20091738","article-title":"IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses","volume":"207","author":"Linterman","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025032411495388100_r39","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1084\/jem.20091777","article-title":"IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism","volume":"207","author":"Zotos","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025032411495388100_r40","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0092-8674(04)00335-6","article-title":"Homeostatic expansion of T cells during immune insufficiency generates autoimmunity","volume":"117","author":"King","year":"2004","journal-title":"Cell"},{"key":"2025032411495388100_r41","doi-asserted-by":"crossref","first-page":"14028","DOI":"10.1073\/pnas.0804358105","article-title":"IL-21 signaling is critical for the development of type I diabetes in the NOD mouse","volume":"105","author":"Spolski","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411495388100_r42","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.2337\/db08-0882","article-title":"Interleukin-21 is required for the development of type 1 diabetes in NOD mice","volume":"58","author":"Sutherland","year":"2009","journal-title":"Diabetes"},{"key":"2025032411495388100_r43","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nature03555","article-title":"A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity","volume":"435","author":"Vinuesa","year":"2005","journal-title":"Nature"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/5\/2730\/61611176\/0903839.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/5\/2730\/61611176\/0903839.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T23:32:50Z","timestamp":1743204770000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/185\/5\/2730\/7977723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,1]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2010,9,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0903839","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,9]]},"published":{"date-parts":[[2010,9,1]]}}}