{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:16:45Z","timestamp":1759961805035,"version":"3.27.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2016,12,19]],"date-time":"2016-12-19T00:00:00Z","timestamp":1482105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2016,12,19]],"date-time":"2016-12-19T00:00:00Z","timestamp":1482105600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"award":["R01AI070101","R01AI124680","R01AI126890","R01 DK062092","VA I01BX001746","ORIP\/OD P51OD011132"],"award-info":[{"award-number":["R01AI070101","R01AI124680","R01AI126890","R01 DK062092","VA I01BX001746","ORIP\/OD P51OD011132"]}]},{"award":["F32DK101163"],"award-info":[{"award-number":["F32DK101163"]}]},{"award":["P30AI050409"],"award-info":[{"award-number":["P30AI050409"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:p>Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T\u2010cell responses. In light of dampened CD8<jats:sup>+<\/jats:sup> T\u2010cell responses, liver disease often manifests systemically as immunoglobulin (Ig)\u2010related syndromes due to aberrant B\u2010cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4<jats:sup>+<\/jats:sup> T\u2010cell help. Elevated CD4<jats:sup>+<\/jats:sup> forkhead box P3\u2013positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8<jats:sup>+<\/jats:sup> T\u2010cell responses, aberrant B\u2010cell activities were maintained due to expression of CD40 ligand on a subset of CD4<jats:sup>+<\/jats:sup> Foxp3+ T cells. <jats:italic toggle=\"yes\">In vivo<\/jats:italic> blockade of CD40 ligand attenuated B\u2010cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4<jats:sup>+<\/jats:sup> Foxp3+, CD40 ligand\u2013positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Liver disease elicits alterations in the intrahepatic CD4<jats:sup>+<\/jats:sup> T\u2010cell compartment that suppress T\u2010cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (H<jats:sc>epatology<\/jats:sc> 2017;65:661\u2010677).<\/jats:p>","DOI":"10.1002\/hep.28894","type":"journal-article","created":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T08:42:42Z","timestamp":1477298562000},"page":"661-677","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T\u2010cell suppression during chronic liver disease"],"prefix":"10.1097","volume":"65","author":[{"given":"Dana","family":"Tedesco","sequence":"first","affiliation":[{"name":"Emory Vaccine Center, Yerkes National Primate Research Center, Division of Microbiology and Immunology, Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj","family":"Thapa","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Yerkes National Primate Research Center, Division of Microbiology and Immunology, Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev","family":"Gumber","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J.","family":"Elrod","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Yerkes National Primate Research Center, Division of Microbiology and Immunology, Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalidur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris C.","family":"Ibegbu","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Yerkes National Primate Research Center, Division of Microbiology and Immunology, Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph F.","family":"Magliocca","sequence":"additional","affiliation":[{"name":"Department of Surgery,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew B.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Surgery,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Anania","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arash","family":"Grakoui","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Yerkes National Primate Research Center, Division of Microbiology and Immunology, Emory University School of Medicine,Atlanta,GA"},{"name":"Division of Infectious Disease,Emory University School of Medicine,Atlanta,GA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2016,12,19]]},"reference":[{"key":"hep28894-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: immune regulation of wound healing in a solid organ","volume":"14","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"hep28894-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","year":"2013","journal-title":"Nat Commun"},{"key":"hep28894-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1172\/JCI66369","article-title":"Hepatic stellate cells in liver development, regeneration, and cancer","volume":"123","year":"2013","journal-title":"J Clin Invest"},{"key":"hep28894-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1002\/hep.27761","article-title":"Liver fibrosis occurs through dysregulation of MyD88\u2010dependent innate B\u2010cell activity","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep28894-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.4049\/jimmunol.1201937","article-title":"Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid","volume":"190","year":"2013","journal-title":"J Immunol"},{"key":"hep28894-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.jhep.2009.12.013","article-title":"Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis","volume":"52","year":"2010","journal-title":"J Hepatol"},{"key":"hep28894-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.21123","article-title":"Liver\u2010targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis","volume":"43","year":"2006","journal-title":"Hepatology"},{"key":"hep28894-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"5549","DOI":"10.4049\/jimmunol.1003917","article-title":"Hepatic stellate cells function as regulatory bystanders","volume":"186","year":"2011","journal-title":"J Immunol"},{"key":"hep28894-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/hep.25765","article-title":"Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep28894-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jhep.2009.10.016","article-title":"Immune\u2010mediated liver injury","volume":"52","year":"2010","journal-title":"J Hepatol"},{"key":"hep28894-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1172\/JCI36604","article-title":"PD\u2010L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT\u20105 phosphorylation in patients chronically infected with HCV","volume":"119","year":"2009","journal-title":"J Clin Invest"},{"key":"hep28894-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"7860","DOI":"10.1128\/JVI.79.12.7860-7867.2005","article-title":"T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus\u2010specific CD8+ T cells during chronic hepatitis C virus infection","volume":"79","year":"2005","journal-title":"J Virol"},{"key":"hep28894-bib-0013-20241017","first-page":"32","article-title":"Rheumatologic manifestations of hepatic diseases","volume":"2","year":"2003","journal-title":"Hepatobiliary Pancreat Dis Int"},{"key":"hep28894-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1002\/hep.27575","article-title":"Systems biological analyses reveal the hepatitis C virus (HCV)\u2010specific regulation of hematopoietic development","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep28894-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","year":"1995","journal-title":"J Hepatol"},{"key":"hep28894-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"3072","DOI":"10.1172\/JCI24798","article-title":"Attenuated liver fibrosis in the absence of B cells","volume":"115","year":"2005","journal-title":"J Clin Invest"},{"key":"hep28894-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11894-001-0044-1","article-title":"Extrahepatic manifestations of chronic viral hepatitis","volume":"3","year":"2001","journal-title":"Curr Gastroenterol Rep"},{"key":"hep28894-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1478-3231.2005.01211.x","article-title":"The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases","volume":"26","year":"2006","journal-title":"Liver Int"},{"key":"hep28894-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ni.1877","article-title":"PD\u20101 regulates germinal center B cell survival and the formation and affinity of long\u2010lived plasma cells","volume":"11","year":"2010","journal-title":"Nat Immunol"},{"key":"hep28894-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ follicular regulatory T cells control the germinal center response","volume":"17","year":"2011","journal-title":"Nat Med"},{"key":"hep28894-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.immuni.2010.11.022","article-title":"Reprogrammed Foxp3+ regulatory t cells provide essential help to support cross\u2010presentation and CD8+ T cell priming in naive mice","volume":"33","year":"2010","journal-title":"Immunity"},{"key":"hep28894-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nri3803","article-title":"A brief history of T cell help to B cells","volume":"15","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"hep28894-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4049\/jimmunol.167.1.21","article-title":"Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus\u2013infected patients","volume":"167","year":"2001","journal-title":"J Immunol"},{"key":"hep28894-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1002\/hep.21060","article-title":"The liver as an immunological organ","volume":"43","year":"2006","journal-title":"Hepatology"},{"key":"hep28894-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nri3700","article-title":"Ectopic lymphoid\u2010like structures in infection, cancer and autoimmunity","volume":"14","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"hep28894-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/hep.510300107","article-title":"Functional B\u2010cell response in intrahepatic lymphoid follicles in chronic hepatitis C","volume":"30","year":"1999","journal-title":"Hepatology"},{"key":"hep28894-bib-0027-20241017","first-page":"520","article-title":"IgG subclasses and allotypes: from structure to effector functions","volume":"5","year":"2014","journal-title":"Front Immunol"},{"key":"hep28894-bib-0028-20241017","first-page":"316","article-title":"A comparative review of toll\u2010like receptor 4 expression and functionality in different animal species","volume":"5","year":"2014","journal-title":"Front Immunol"},{"key":"hep28894-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/cmi.2015.12","article-title":"Regulatory T cells turn pathogenic","volume":"12","year":"2015","journal-title":"Cell Mol Immunol"},{"key":"hep28894-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.immuni.2011.12.012","article-title":"Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells","volume":"36","year":"2012","journal-title":"Immunity"},{"key":"hep28894-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ni1455","article-title":"Foxp3 in control of the regulatory T cell lineage","volume":"8","year":"2007","journal-title":"Nat Immunol"},{"key":"hep28894-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/ni1437","article-title":"Maintenance of the Foxp3\u2010dependent developmental program in mature regulatory T cells requires continued expression of Foxp3","volume":"8","year":"2007","journal-title":"Nat Immunol"},{"key":"hep28894-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/ng1599","article-title":"Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans","volume":"37","year":"2005","journal-title":"Nat Genet"},{"key":"hep28894-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1002\/eji.200939392","article-title":"CD46\u2010induced human Treg enhance B\u2010cell responses","volume":"39","year":"2009","journal-title":"Eur J Immunol"},{"key":"hep28894-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1182\/blood-2005-07-2951","article-title":"Complement\u2010induced regulatory T cells suppress T\u2010cell responses but allow for dendritic\u2010cell maturation","volume":"107","year":"2006","journal-title":"Blood"},{"key":"hep28894-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1146\/annurev.micro.58.030603.123836","article-title":"Cell\u2010mediated immunity and the outcome of hepatitis C virus infection","volume":"58","year":"2004","journal-title":"Annu Rev Microbiol"},{"key":"hep28894-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"hep28894-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1128\/jvi.70.12.8375-8381.1996","article-title":"CD40 ligand\u2010deficient mice generate a normal primary cytotoxic T\u2010lymphocyte response but a defective humoral response to a viral infection","volume":"70","year":"1996","journal-title":"J Virol"},{"key":"hep28894-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.4049\/jimmunol.160.5.2158","article-title":"Anti\u2010CD40 ligand antibody treatment of SNF1 mice with established nephritis: preservation of kidney function","volume":"160","year":"1998","journal-title":"J Immunol"},{"key":"hep28894-bib-0040-20241017","first-page":"114","article-title":"Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand","volume":"6","year":"2000","journal-title":"Nat Med"},{"key":"hep28894-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.4049\/jimmunol.0903888","article-title":"Anti\u2010CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice","volume":"185","year":"2010","journal-title":"J Immunol"},{"key":"hep28894-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s13075-015-0757-4","article-title":"CDP7657, an anti\u2010CD40L antibody lacking an Fc domain, inhibits CD40L\u2010dependent immune responses without thrombotic complications: an in vivo study","volume":"17","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"hep28894-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.jhep.2013.05.034","article-title":"Regulatory T\u2010cell directed therapies in liver diseases","volume":"59","year":"2013","journal-title":"J Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28894","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28894","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.28894","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.28894","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201702000-00025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:34:11Z","timestamp":1729211651000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201702000-00025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,19]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.28894","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"type":"print","value":"0270-9139"},{"type":"electronic","value":"1527-3350"}],"subject":[],"published":{"date-parts":[[2016,12,19]]},"assertion":[{"value":"2016-05-27","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-10-05","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}