{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T09:27:26Z","timestamp":1793179646378,"version":"4.5.0"},"reference-count":45,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,6,18]]},"abstract":"<jats:p>The T helper (Th) cell pool is composed of specialized cells with heterogeneous effector functions. Apart from Th1 and 2 cells, CXCR5+ T cells have been suggested to be another type of effector T cell specialized for B cell help. We show here that CXCR5+ T cells are heterogeneous, and we identify subsets of CXCR5+ CD4 T cells that differ in function and microenvironmental localization in secondary lymphoid tissues. CD57+CXCR5 T cells, hereafter termed germinal center Th (GC-Th) cells, are localized only in GCs, lack CCR7, and are highly responsive to the follicular chemokine B lymphocyte chemoattractant but not to the T cell zone EBI1-ligand chemokine. Importantly, GC-Th cells are much more efficient than CD57\u2212CXCR5+ T cells or CXCR5\u2212 T cells in inducing antibody production from B cells. Consistent with their function, GC-Th cells produce elevated levels of interleukin 10 upon stimulation which, with other cytokines and costimulatory molecules, may help confer their B cell helper activity. Our results demonstrate that CXCR5+ T cells are functionally heterogeneous and that the GC-Th cells, a small subset of CXCR5+ T cells, are the key helpers for B cell differentiation and antibody production in lymphoid tissues.<\/jats:p>","DOI":"10.1084\/jem.193.12.1373","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"1373-1382","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":561,"title":["Subspecialization of Cxcr5+ T Cells"],"prefix":"10.1084","volume":"193","author":[{"given":"Chang H.","family":"Kim","sequence":"first","affiliation":[{"name":"aLaboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305"},{"name":"bCenter for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusijah S.","family":"Rott","sequence":"additional","affiliation":[{"name":"aLaboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305"},{"name":"bCenter for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Clark-Lewis","sequence":"additional","affiliation":[{"name":"cBiomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada BC V6T 1Z3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Campbell","sequence":"additional","affiliation":[{"name":"aLaboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305"},{"name":"bCenter for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wu","sequence":"additional","affiliation":[{"name":"dMillennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene C.","family":"Butcher","sequence":"additional","affiliation":[{"name":"aLaboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305"},{"name":"bCenter for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2001,6,18]]},"reference":[{"key":"2023072509372481800_R1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF02786482","article-title":"Function and regulation of memory CD4 T cells","volume":"19","author":"Metz","year":"1999","journal-title":"Immunol. 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Med."},{"key":"2023072509372481800_R18","doi-asserted-by":"crossref","first-page":"5671","DOI":"10.4049\/jimmunol.159.11.5671","article-title":"Identification of a new mouse \u03b2-chemokine, thymus-derived chemotactic agent 4, with activity on T lymphocytes and mesangial cells","volume":"159","author":"Tanabe","year":"1997","journal-title":"J. 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Opin. Immunol."},{"key":"2023072509372481800_R24","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1006\/smim.1997.0080","article-title":"Regulation of B-cell commitment to plasma cells or to memory B cells","volume":"9","author":"Liu","year":"1997","journal-title":"Semin. 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Med."},{"key":"2023072509372481800_R34","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.184.2.473","article-title":"Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level","volume":"184","author":"Sornasse","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509372481800_R35","first-page":"439","article-title":"The distribution and possible significance of cells identified in human lymphoid tissue by the monoclonal antibody HNK-1","volume":"51","author":"Ritchie","year":"1983","journal-title":"Clin. Exp. Immunol."},{"key":"2023072509372481800_R36","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/BF00918700","article-title":"Isolation and characterization of Leu 71 germinal-center cells with the T helper-cell phenotype and granular lymphocyte morphology","volume":"6","author":"Velardi","year":"1986","journal-title":"J. Clin. Immunol."},{"key":"2023072509372481800_R37","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0198-8859(91)90050-J","article-title":"Germinal center T cells are distinct helper-inducer T cells","volume":"31","author":"Bowen","year":"1991","journal-title":"Hum. Immunol."},{"key":"2023072509372481800_R38","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1126\/science.286.5447.2159","article-title":"The role of CCR7 in TH1 and TH2 cell localization and delivery of B cell help in vivo","volume":"286","author":"Randolph","year":"1999","journal-title":"Science."},{"key":"2023072509372481800_R39","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/1074-7613(95)90031-4","article-title":"Cross-linking of OX40 ligand, a member of the TNF\/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells","volume":"2","author":"Stuber","year":"1995","journal-title":"Immunity."},{"key":"2023072509372481800_R40","doi-asserted-by":"crossref","first-page":"5261","DOI":"10.4049\/jimmunol.151.10.5261","article-title":"Cloning of mouse Ox40a T cell activation marker that may mediate T-B cell interactions","volume":"151","author":"Calderhead","year":"1993","journal-title":"J. Immunol."},{"key":"2023072509372481800_R41","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0008-8749(77)90143-5","article-title":"Human B-cell activation in vitro. T cell-dependent pokeweed mitogen-induced differentiation of blood B lymphocytes","volume":"33","author":"Gmelig-Meyling","year":"1977","journal-title":"Cell. Immunol."},{"key":"2023072509372481800_R42","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.4049\/jimmunol.140.11.3736","article-title":"T cell-dependent activation of B cell proliferation and differentiation by immobilized monoclonal antibodies to CD3","volume":"140","author":"Hirohata","year":"1988","journal-title":"J. Immunol."},{"key":"2023072509372481800_R43","doi-asserted-by":"crossref","first-page":"F31","DOI":"10.1084\/jem.192.11.F31","article-title":"Follicular homing T helper (Th) cells and the Th1\/Th2 paradigm","volume":"192","author":"Mackay","year":"2000","journal-title":"J. Exp. 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