{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:10:44Z","timestamp":1769645444280,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2008,9,1]],"date-time":"2008-09-01T00:00:00Z","timestamp":1220227200000},"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":[[2008,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4+ T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4+ T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-\u03b3-producing CD4+ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-\u03b3-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4+ T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4+ T cells in the target organ.<\/jats:p>","DOI":"10.4049\/jimmunol.181.6.4381","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:24:33Z","timestamp":1397849073000},"page":"4381-4388","source":"Crossref","is-referenced-by-count":12,"title":["4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease"],"prefix":"10.1093","volume":"181","author":[{"given":"Douglas G","family":"Mack","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison K","family":"Lanham","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brent E","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa A","family":"Maier","sequence":"additional","affiliation":[{"name":"Department of Medicine"},{"name":"Department of Medicine, National Jewish Medical and Research Center , Denver, CO 80206"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania H","family":"Watts","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P","family":"Fontenot","sequence":"additional","affiliation":[{"name":"Department of Medicine"},{"name":"Department of Immunology, University of Colorado Denver , Denver, CO 80262"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2008,9,15]]},"reference":[{"key":"2026012807081547500_R1","first-page":"555","article-title":"New perspectives of CD28\u2013B7-mediated T cell costimulation","volume-title":"Immunity","year":"1995"},{"key":"2026012807081547500_R2","first-page":"211","article-title":"Role of the CD28 receptor in T-cell activation","volume-title":"Immunol. Today","year":"1990"},{"key":"2026012807081547500_R3","first-page":"11094","article-title":"Costimulation of T-cell activation and virus production by B7 antigen on activated CD4+ T cells from human immunodeficiency virus type 1-infected donors","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1993"},{"key":"2026012807081547500_R4","first-page":"725","article-title":"Decreased dependence of myelin basic protein-reactive T cells on CD28- mediated costimulation in multiple sclerosis patients: a marker of activated\/memory T cells","volume-title":"J. Clin. Invest.","year":"1998"},{"key":"2026012807081547500_R5","first-page":"1185","article-title":"CD4+CD28\u2212 costimulation-independent T cells in multiple sclerosis","volume-title":"J. Clin. Invest.","year":"2001"},{"key":"2026012807081547500_R6","first-page":"2027","article-title":"CD4+ CD7\u2212 CD28\u2212 T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity","volume-title":"J. Clin. Invest.","year":"1996"},{"key":"2026012807081547500_R7","first-page":"8119","article-title":"Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity","volume-title":"J. Biol. Chem.","year":"1998"},{"key":"2026012807081547500_R8","first-page":"1540","article-title":"Highly activated T-cell receptor AV2S3+ CD4+ lung T-cell expansions in pulmonary sarcoidosis","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2001"},{"key":"2026012807081547500_R9","first-page":"776","article-title":"CD28 costimulation independence of target organ versus circulating memory antigen-specific CD4+ T cells","volume-title":"J. Clin. Invest.","year":"2003"},{"key":"2026012807081547500_R10","first-page":"481","article-title":"Role of 4-1BB in immune responses","volume-title":"Semin. Immunol.","year":"1998"},{"key":"2026012807081547500_R11","first-page":"23","article-title":"TNF\/TNFR family members in costimulation of T cell responses","volume-title":"Annu. Rev. Immunol.","year":"2005"},{"key":"2026012807081547500_R12","first-page":"275","article-title":"Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells","volume-title":"Int. Immunol.","year":"2002"},{"key":"2026012807081547500_R13","first-page":"37","article-title":"4-1BB-ligand is regulated on human dendritic cells and induces the production of IL-12","volume-title":"Cell. Immunol.","year":"2003"},{"key":"2026012807081547500_R14","first-page":"1313","article-title":"4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy","volume-title":"J. Immunol.","year":"2001"},{"key":"2026012807081547500_R15","first-page":"881","article-title":"Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012807081547500_R16","first-page":"4897","article-title":"4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807081547500_R17","first-page":"551","article-title":"Costimulation of CD28\u2212 T lymphocytes by 4-1BB ligand","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012807081547500_R18","first-page":"446","article-title":"Costimulation of human CD28- T cells by 4-1BB ligand","volume-title":"Eur. J. Immunol.","year":"2003"},{"key":"2026012807081547500_R19","first-page":"1291","article-title":"Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2026012807081547500_R20","first-page":"6378","article-title":"Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012807081547500_R21","first-page":"6368","article-title":"Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T cell responses: comparison with B7.1 and 4-1BBL","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012807081547500_R22","first-page":"543","article-title":"Genetic susceptibility and immune-mediated destruction in beryllium-induced disease","volume-title":"Trends Immunol.","year":"2005"},{"key":"2026012807081547500_R23","first-page":"937S","article-title":"The natural history of beryllium sensitization and chronic beryllium disease","volume-title":"Environ. Health Perspect.","year":"1996"},{"key":"2026012807081547500_R24","first-page":"4","article-title":"Chronic beryllium disease: T cell recognition of a metal presented by HLA-DP","volume-title":"Clin. Immunol.","year":"2001"},{"key":"2026012807081547500_R25","first-page":"1473","article-title":"Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease","volume-title":"J. Clin. Invest.","year":"2002"},{"key":"2026012807081547500_R26","first-page":"687","article-title":"Proliferative response of bronchoalveolar lymphocytes to beryllium","volume-title":"Ann. Intern. Med.","year":"1988"},{"key":"2026012807081547500_R27","first-page":"1103","article-title":"Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells","volume-title":"N. Engl. J. Med.","year":"1989"},{"key":"2026012807081547500_R28","first-page":"603","article-title":"Screening blood test identifies subclinical beryllium disease","volume-title":"J. Occup. Med.","year":"1989"},{"key":"2026012807081547500_R29","first-page":"267","article-title":"Beryllium disease screening in the ceramics industry: blood test performance and exposure-disease relations","volume-title":"J. Occup. Med.","year":"1993"},{"key":"2026012807081547500_R30","first-page":"54","article-title":"Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease","volume-title":"J. Allergy Clin. Immunol.","year":"1991"},{"key":"2026012807081547500_R31","first-page":"953S","article-title":"Significance of the blood beryllium lymphocyte proliferation test","volume-title":"Environ. Health Perspect.","year":"1996"},{"key":"2026012807081547500_R32","first-page":"518","article-title":"Beryllium induces IL-2 and IFN-\u03b3 in berylliosis","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012807081547500_R33","first-page":"1479","article-title":"Pathologic and immunologic alterations in early stages of beryllium disease: re-examination of disease definition and natural history","volume-title":"Am. Rev. Respir. Dis.","year":"1989"},{"key":"2026012807081547500_R34","first-page":"581","article-title":"Expansions of T-cell subsets expressing particular T cell receptor variable regions in chronic beryllium disease","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"1998"},{"key":"2026012807081547500_R35","first-page":"1019","article-title":"Identification of pathogenic T cells in patients with beryllium-induced lung disease","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012807081547500_R36","first-page":"12717","article-title":"Beryllium presentation to CD4+ T cells underlies disease susceptibility HLA-DP alleles in chronic beryllium disease","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2000"},{"key":"2026012807081547500_R37","first-page":"2704","article-title":"Up-regulation of programmed death-1 expression on beryllium-specific CD4+ T cells in chronic beryllium disease","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012807081547500_R38","first-page":"2886","article-title":"Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response","volume-title":"J. Clin. Invest.","year":"2005"},{"key":"2026012807081547500_R39","first-page":"1405","article-title":"Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012807081547500_R40","first-page":"843","article-title":"Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major","volume-title":"Nat. Med.","year":"2007"},{"key":"2026012807081547500_R41","first-page":"184","article-title":"CD57 expression correlates with alveolitis severity in subjects with beryllium-induced disease","volume-title":"J. Allergy Clin. Immunol.","year":"2007"},{"key":"2026012807081547500_R42","first-page":"1036","article-title":"Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease","volume-title":"J. Allergy Clin. Immunol.","year":"2005"},{"key":"2026012807081547500_R43","first-page":"805","article-title":"Exploring pathways for memory T cell generation","volume-title":"J. Clin. Invest.","year":"2001"},{"key":"2026012807081547500_R44","first-page":"3360","article-title":"Potential role of 4-1BB in T cell activation: comparison with the costimulatory molecule CD28","volume-title":"J. Immunol.","year":"1995"},{"key":"2026012807081547500_R45","first-page":"3253","article-title":"Role of 4-1BB (CD137) in the functional activation of cord blood CD28\u2212CD8+ T cells","volume-title":"Blood","year":"2002"},{"key":"2026012807081547500_R46","first-page":"3777","article-title":"Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807081547500_R47","first-page":"4882","article-title":"4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807081547500_R48","first-page":"2281","article-title":"PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection","volume-title":"J. Exp. Med.","year":"2006"},{"key":"2026012807081547500_R49","first-page":"1218","article-title":"Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas","volume-title":"J. Occup. Environ. Med.","year":"2005"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/6\/4381\/62580172\/7777.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/6\/4381\/62580172\/7777.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:09:20Z","timestamp":1769602160000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/6\/4381\/8008021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2008,9,15]]},"published-print":{"date-parts":[[2008,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.6.4381","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,9]]},"published":{"date-parts":[[2008,9]]}}}