{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:57:19Z","timestamp":1791176239594,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2015,6,1]],"date-time":"2015-06-01T00:00:00Z","timestamp":1433116800000},"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":[[2015,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1+ CD44highCD4+ T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1+ CD44highCD4+ T cells develop as unique T follicular (TF) cells in a B cell\u2013dependent manner and consist of two subpopulations, as follows: CD153+ cells preferentially secreting abundant osteopontin on TCR stimulation and CD153\u2212 cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4+ T cell proliferation in vivo, suggesting replicative senescence. Although the CD153+ TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor\u2013induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153+ PD-1+ CD4+ T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153+ TF cells generated as a consequence of extensive endogenous CD4+ T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.<\/jats:p>","DOI":"10.4049\/jimmunol.1500319","type":"journal-article","created":{"date-parts":[[2015,5,14]],"date-time":"2015-05-14T02:42:37Z","timestamp":1431571357000},"page":"5725-5735","source":"Crossref","is-referenced-by-count":114,"title":["A CD153+CD4+ T Follicular Cell Population with Cell-Senescence Features Plays a Crucial Role in Lupus Pathogenesis via Osteopontin Production"],"prefix":"10.1093","volume":"194","author":[{"given":"Suhail","family":"Tahir","sequence":"first","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyosuke","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harumi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Uede","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University , Sapporo 060-0815 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Hamazaki","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Hattori","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagahiro","family":"Minato","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,6,15]]},"reference":[{"key":"2025030706502501400_r1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1600-065X.1986.tb01484.x","article-title":"Antigen-driven selection of virgin and memory B cells","volume":"91","author":"MacLennan","year":"1986","journal-title":"Immunol. Rev."},{"key":"2025030706502501400_r2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.it.2012.04.003","article-title":"Determining germinal centre B cell fate","volume":"33","author":"Zotos","year":"2012","journal-title":"Trends Immunol."},{"key":"2025030706502501400_r3","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/367425a0","article-title":"How B and T cells talk to each other","volume":"367","author":"Clark","year":"1994","journal-title":"Nature"},{"key":"2025030706502501400_r4","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nri2644","article-title":"New insights into the differentiation and function of T follicular helper cells","volume":"9","author":"King","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030706502501400_r5","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":"2025030706502501400_r6","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":"2025030706502501400_r7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/imr.12031","article-title":"T-cell subsets in the germinal center","volume":"252","author":"Ramiscal","year":"2013","journal-title":"Immunol. Rev."},{"key":"2025030706502501400_r8","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1172\/JCI200319301","article-title":"Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions","volume":"112","author":"Grammer","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2025030706502501400_r9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nri2637","article-title":"Dysregulation of germinal centres in autoimmune disease","volume":"9","author":"Vinuesa","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030706502501400_r10","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/nm.2752","article-title":"Taming lupus: a new understanding of pathogenesis is leading to clinical advances","volume":"18","author":"Liu","year":"2012","journal-title":"Nat. Med."},{"key":"2025030706502501400_r11","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1073\/pnas.97.12.6670","article-title":"Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains","volume":"97","author":"Morel","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030706502501400_r12","doi-asserted-by":"crossref","first-page":"4852","DOI":"10.2741\/3044","article-title":"B lymphocytes\u2014chief players and therapeutic targets in autoimmune diseases","volume":"13","author":"Zouali","year":"2008","journal-title":"Front. Biosci."},{"key":"2025030706502501400_r13","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1172\/JCI24179","article-title":"Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus","volume":"115","author":"Cappione","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2025030706502501400_r14","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.1600-065X.1998.tb01220.x","article-title":"B-cell epitope spreading in autoimmunity","volume":"164","author":"James","year":"1998","journal-title":"Immunol. Rev."},{"key":"2025030706502501400_r15","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature09370","article-title":"Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance","volume":"467","author":"Kim","year":"2010","journal-title":"Nature"},{"key":"2025030706502501400_r16","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1084\/jem.20081886","article-title":"Follicular helper T cells are required for systemic autoimmunity","volume":"206","author":"Linterman","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025030706502501400_r17","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/art.25032","article-title":"Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus","volume":"62","author":"Simpson","year":"2010","journal-title":"Arthritis Rheum."},{"key":"2025030706502501400_r18","doi-asserted-by":"crossref","first-page":"15807","DOI":"10.1073\/pnas.0908805106","article-title":"PD-1+ memory phenotype CD4+ T cells expressing C\/EBPalpha underlie T cell immunodepression in senescence and leukemia","volume":"106","author":"Shimatani","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030706502501400_r19","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1096\/fj.12-226951","article-title":"Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor","volume":"27","author":"Keszei","year":"2013","journal-title":"FASEB J."},{"key":"2025030706502501400_r20","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/0014-4827(91)90430-3","article-title":"Establishment of a germ-line competent C57BL\/6 embryonic stem cell line","volume":"197","author":"Ledermann","year":"1991","journal-title":"Exp. Cell Res."},{"key":"2025030706502501400_r21","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.4049\/jimmunol.1000024","article-title":"CD30 ligand\/CD30 plays a critical role in Th17 differentiation in mice","volume":"185","author":"Sun","year":"2010","journal-title":"J. Immunol."},{"key":"2025030706502501400_r22","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1002\/jbmr.495","article-title":"Crucial role of the cryptic epitope SLAYGLR within osteopontin in renal crystal formation of mice","volume":"26","author":"Hamamoto","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"2025030706502501400_r23","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/intimm\/dxp112","article-title":"IL-21 and T follicular helper cells","volume":"22","author":"Spolski","year":"2010","journal-title":"Int. Immunol."},{"key":"2025030706502501400_r24","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrm2233","article-title":"Cellular senescence: when bad things happen to good cells","volume":"8","author":"Campisi","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025030706502501400_r25","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/nm.2963","article-title":"Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity","volume":"18","author":"Li","year":"2012","journal-title":"Nat. Med."},{"key":"2025030706502501400_r26","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0092-8674(03)00401-X","article-title":"Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence","volume":"113","author":"Narita","year":"2003","journal-title":"Cell"},{"key":"2025030706502501400_r27","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1158\/0008-5472.CAN-03-1337","article-title":"CD30 is involved in inhibition of T-cell proliferation by Hodgkin\u2019s Reed-Sternberg cells","volume":"64","author":"Su","year":"2004","journal-title":"Cancer Res."},{"key":"2025030706502501400_r28","doi-asserted-by":"crossref","first-page":"6032","DOI":"10.1182\/blood-2011-12-399089","article-title":"Targeting antiapoptotic A1\/Bfl-1 by in vivo RNAi reveals multiple roles in leukocyte development in mice","volume":"119","author":"Ottina","year":"2012","journal-title":"Blood"},{"key":"2025030706502501400_r29","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.molmed.2010.03.003","article-title":"Inflammatory networks during cellular senescence: causes and consequences","volume":"16","author":"Freund","year":"2010","journal-title":"Trends Mol. Med."},{"key":"2025030706502501400_r30","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/ni.2018","article-title":"Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells","volume":"12","author":"Sprent","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030706502501400_r31","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":"2025030706502501400_r32","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.it.2004.11.006","article-title":"The new paradigm of T-cell homeostatic proliferation-induced autoimmunity","volume":"26","author":"Baccala","year":"2005","journal-title":"Trends Immunol."},{"key":"2025030706502501400_r33","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1146\/annurev.immunol.21.120601.141110","article-title":"T cell anergy","volume":"21","author":"Schwartz","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"2025030706502501400_r34","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/j.0105-2896.2005.00241.x","article-title":"T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens","volume":"204","author":"Lohr","year":"2005","journal-title":"Immunol. Rev."},{"key":"2025030706502501400_r35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.smim.2006.12.005","article-title":"Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors","volume":"19","author":"Christensen","year":"2007","journal-title":"Semin. Immunol."},{"key":"2025030706502501400_r36","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S1074-7613(00)80089-8","article-title":"Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor","volume":"11","author":"Nishimura","year":"1999","journal-title":"Immunity"},{"key":"2025030706502501400_r37","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cytogfr.2008.08.001","article-title":"Osteopontin: role in immune regulation and stress responses","volume":"19","author":"Wang","year":"2008","journal-title":"Cytokine Growth Factor Rev."},{"key":"2025030706502501400_r38","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ng.749","article-title":"Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity","volume":"43","author":"Lausch","year":"2011","journal-title":"Nat. Genet."},{"key":"2025030706502501400_r39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ni1415","article-title":"Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells","volume":"8","author":"Hur","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025030706502501400_r40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/ni.3050","article-title":"A p85\u03b1-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells","volume":"16","author":"Leavenworth","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025030706502501400_r41","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.4049\/jimmunol.0901652","article-title":"Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB\/W F1 mice","volume":"184","author":"Kasagi","year":"2010","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/12\/5725\/62236474\/1500319.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/12\/5725\/62236474\/1500319.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:33:19Z","timestamp":1741332799000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/194\/12\/5725\/7960789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2015,6,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1500319","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,6]]},"published":{"date-parts":[[2015,6]]}}}