{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:20:44Z","timestamp":1793395244205,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>T Follicular helper (Tfh) cells, recognized as a distinct CD4<jats:sup>+<\/jats:sup> T cell subset, mediate the development of long-lived humoral immunity <jats:italic>via<\/jats:italic> B cell activation\/differentiation. Tfh cells play an important role during hepatic viral infection, but its role in hepatitis B virus-related acute on chronic liver failure (HBV-ACLF) remains to be explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>The frequency of Tfh cells, serum pro-inflammatory cytokine (IL-12, IL-21, IL-17 and TNF) levels and IgG\/M levels were investigated in HBV-ACLF (n = 36), serious chronic hepatitis B (n = 21), moderate chronic hepatitis B patients (n = 32) and healthy control (HC) subjects (n = 10).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Circulating Tfh cells were significantly increased in HBV-ACLF patients compared to other groups, correlating well with MELD score. However, the frequency of Tfh cells decreased in ameliorated HBV-ACLF patients. Furthermore, serum IL-12 and IL-21 levels were higher in HBV-ACLF patients, compared to other groups. Na\u00efve CD4<jats:sup>+<\/jats:sup> T cells from HC subjects differentiate into Tfh cells following treatment with HBV-ACLF patients\u2019 serum, a process that can be blocked by IL-12\/21 neutralizing antibodies. Tfh cells induced by HBV-ACLF patient\u2019s serum promoted the proliferation and IgG production of B cells <jats:italic>in vitro<\/jats:italic>. Moreover, circulating CD19<jats:sup>+<\/jats:sup> B cells, serum and liver IgG\/M levels were significantly higher in HBV-ACLF patients, compared to other groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data demonstrated that there was a high frequency of Tfh cells and high levels of serum IL-12\/21 in HBV-ACLF patients. Na\u00efve CD4<jats:sup>+<\/jats:sup> T cells differentiate into Tfh cells in the presence of HBV-ACLF patients\u2019 serum rich in IL-12\/21, which can be blocked by neutralizing IL-12\/21 antibodies. These data may provide useful insights for both clinical and basic research in the treatment of HBV-ACLF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.641362","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T05:02:47Z","timestamp":1617166967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Increased Circulating T Follicular Helper Cells Induced via IL-12\/21 in Patients With Acute on Chronic Hepatitis B Liver Failure"],"prefix":"10.3389","volume":"12","author":[{"given":"Bingying","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongkun","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingwang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-019-09946-3","article-title":"Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update","volume":"13","author":"Sarin","year":"2019","journal-title":"Hepatol Int"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-010-9416-3","article-title":"Involvement of Th17 and Th1 effector responses in patients with Hepatitis B","volume":"30","author":"Ye","year":"2010","journal-title":"J Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/hep.23273","article-title":"Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B","volume":"51","author":"Zhang","year":"2010","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2018.3946","article-title":"Next generation sequencing reveals novel alterations in B-cell heavy chain receptor repertoires associated with acute-on-chronic liver failure","volume":"43","author":"Yan","year":"2019","journal-title":"Int J Mol Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120994","article-title":"The origins, function, and regulation of T follicular helper cells","volume":"209","author":"Ma","year":"2012","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00520","article-title":"Regulators of Tfh Cell Differentiation","volume":"7","author":"Jogdand","year":"2016","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13282","article-title":"Functional differentiation and regulation of follicular T helper cells in inflammation and autoimmunity","author":"Dong","year":"2020","journal-title":"Immunology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/art.41672","article-title":"Specific T follicular helper signature in Takayasu Arteritis","author":"Desbois","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3054","article-title":"Pathophysiology of T follicular helper cells in humans and mice","volume":"16","author":"Ueno","year":"2015","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2366","article-title":"IL-12 family cytokines: immunological playmakers","volume":"13","author":"Vignali","year":"2012","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2019.01.013","article-title":"Clinical significance and immunobiology of IL-21 in autoimmunity","volume":"99","author":"Long","year":"2019","journal-title":"J Autoimmun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44198","article-title":"IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B","volume":"121","author":"Publicover","year":"2011","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/liv.13475","article-title":"Immune correlates of hepatitis B surface antigen spontaneous seroconversion in hepatitis B e antigen negative chronic hepatitis B patients","volume":"38","author":"Vyas","year":"2018","journal-title":"Liver Int"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-396648","article-title":"Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1\/09 vaccine","volume":"120","author":"Pallikkuth","year":"2012","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41419-018-0670-2","article-title":"Enhancer of zeste homolog 2-catalysed H3K27 trimethylation plays a key role in acute-on-chronic liver failure via TNF-mediated pathway","volume":"9","author":"Zhou","year":"2018","journal-title":"Cell Death Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.14634","article-title":"N-myc and STAT interactor correlates with severity and prognosis in acute-on-chronic liver failure of hepatitis B virus","volume":"34","author":"Xiong","year":"2019","journal-title":"J Gastroenterol Hepatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1053\/jlts.2002.35927","article-title":"The new liver allocation system: moving toward evidence-based transplantation policy","volume":"8","author":"Freeman","year":"2002","journal-title":"Liver Transpl"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217646","article-title":"Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sj\u00f6gren\u2019s syndrome with ectopic germinal centres and MALT lymphoma","volume":"79","author":"Pontarini","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.016","article-title":"Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12","volume":"31","author":"Schmitt","year":"2009","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31695","article-title":"Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: re-modelling of antiviral and regulatory mediators","author":"Amin","year":"2020","journal-title":"Hepatol (Baltimore Md)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-11-54","article-title":"Expansion of circulating TFH cells and their associated molecules: involvement in the immune landscape in patients with chronic HBV infection","volume":"11","author":"Hu","year":"2014","journal-title":"Virol J"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.11.1553","article-title":"CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function","volume":"192","author":"Schaerli","year":"2000","journal-title":"J Exp Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/art.40556","article-title":"Aberrant Expansion and Function of Follicular Helper T Cell Subsets in IgG4-Related Disease","volume":"70","author":"Chen","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v26.i31.4703","article-title":"Mucosal-associated invariant T cells in hepatitis B virus-related liver failure","volume":"26","author":"Xue","year":"2020","journal-title":"World J Gastroenterol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2893.2011.01475.x","article-title":"Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease","volume":"18","author":"Hu","year":"2011","journal-title":"J Viral Hepat"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01637","article-title":"T Follicular Helper Cells in Autoimmune Disorders","volume":"9","author":"Gensous","year":"2018","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.17179\/excli2020-3104","article-title":"Immunology of IL-12: An update on functional activities and implications for disease","volume":"19","author":"Ullrich","year":"2020","journal-title":"EXCLI J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1478-3231.2011.02654.x","article-title":"Activated lymphocytes and high liver expression of IFN-gamma are associated with fulminant hepatic failure in patients","volume":"32","author":"dos Santos","year":"2012","journal-title":"Liver Int"},{"key":"B31","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.toxlet.2018.04.021","article-title":"IL-17 deficiency attenuates acetaminophen-induced hepatotoxicity in mice","volume":"292","author":"Lee","year":"2018","journal-title":"Toxicol Lett"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02013","article-title":"Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics","volume":"11","author":"Khanam","year":"2020","journal-title":"Front Immunol"}],"updated-by":[{"DOI":"10.3389\/fimmu.2022.798058","type":"addendum","label":"Addendum","source":"publisher","updated":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.641362\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T05:02:51Z","timestamp":1617166971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.641362\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,31]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2021.641362"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.641362","relation":{"addendum":[{"id-type":"doi","id":"10.3389\/fimmu.2022.798058","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,31]]},"article-number":"641362"}}