{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:36:13Z","timestamp":1790429773714,"version":"4.1.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T00:00:00Z","timestamp":1448323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0143715","type":"journal-article","created":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T16:42:23Z","timestamp":1448383343000},"page":"e0143715","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis"],"prefix":"10.1371","volume":"10","author":[{"given":"Ira","family":"an Haack","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Derkow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Riehn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Nicolas","family":"Rentinck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja A.","family":"K\u00fchl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seija","family":"Lehnardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckart","family":"Schott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,11,24]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1056\/NEJMra050408","article-title":"Autoimmune hepatitis","volume":"354","author":"EL Krawitt","year":"2006","journal-title":"N Engl J Med"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.3748\/wjg.14.3306","article-title":"Aetiopathogenesis of autoimmune hepatitis","volume":"14","author":"D Vergani","year":"2008","journal-title":"World journal of gastroenterology: WJG"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1053\/j.gastro.2014.04.022","article-title":"Genome-wide association study identifies variants associated with autoimmune hepatitis type 1","volume":"147","author":"YS de Boer","year":"2014","journal-title":"Gastroenterology"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1002\/hep.22167","article-title":"Dendritic cells are required for effective cross-presentation in the murine liver","volume":"47","author":"G Plitas","year":"2008","journal-title":"Hepatology"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/hep.22395","article-title":"Mechanism of T cell tolerance induction by murine hepatic Kupffer cells","volume":"48","author":"Q You","year":"2008","journal-title":"Hepatology (Baltimore, Md)"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/82161","article-title":"Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance","volume":"6","author":"A Limmer","year":"2000","journal-title":"Nat Med"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.immuni.2006.11.011","article-title":"Ito cells are liver-resident antigen-presenting cells for activating T cell responses","volume":"26","author":"F Winau","year":"2007","journal-title":"Immunity"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"5430","DOI":"10.4049\/jimmunol.166.9.5430","article-title":"Antigen-specific primary activation of CD8+ T cells within the liver","volume":"166","author":"P Bertolino","year":"2001","journal-title":"J Immunol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1002\/hep.21796","article-title":"Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis","volume":"46","author":"K Derkow","year":"2007","journal-title":"Hepatology"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.4049\/jimmunol.177.3.1689","article-title":"Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation","volume":"177","author":"SA Wuensch","year":"2006","journal-title":"J Immunol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1002\/eji.1830250721","article-title":"Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver","volume":"25","author":"P Bertolino","year":"1995","journal-title":"Eur J Immunol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.celrep.2013.02.008","article-title":"Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity","volume":"3","author":"JP B\u00f6ttcher","year":"2013","journal-title":"Cell reports"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e21847","DOI":"10.1371\/journal.pone.0021847","article-title":"Failure of CD4 T-cells to respond to liver-derived antigen and to provide help to CD8 T-cells","volume":"6","author":"K Derkow","year":"2011","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/hep.23745","article-title":"Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes","volume":"52","author":"SA Wuensch","year":"2010","journal-title":"Hepatology"},{"key":"ref15","first-page":"2087","article-title":"Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells","volume":"193","author":"SS Tay","year":"2014","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1002\/hep.23191","article-title":"Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3- regulatory T cells suppressing autoimmune hepatitis","volume":"50","author":"N Kruse","year":"2009","journal-title":"Hepatology"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"5574","DOI":"10.4049\/jimmunol.1300826","article-title":"Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells","volume":"191","author":"S Burghardt","year":"2013","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.jhep.2014.04.027","article-title":"TGF-beta-dependent induction of CD4(+)CD25(+)Foxp3(+) Tregs by liver sinusoidal endothelial cells","volume":"61","author":"A Carambia","year":"2014","journal-title":"Journal of hepatology"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/j.transproceed.2013.03.015","article-title":"PD-L1 signal on liver dendritic cells is critical for Foxp3(+)CD4(+)CD25(+) Treg and liver tolerance induction in mice","volume":"45","author":"H Liu","year":"2013","journal-title":"Transplantation proceedings"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"S Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.immuni.2013.03.002","article-title":"Development and maintenance of regulatory T cells","volume":"38","author":"N Ohkura","year":"2013","journal-title":"Immunity"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.immuni.2009.04.010","article-title":"Mechanisms of foxp3+ T regulatory cell-mediated suppression","volume":"30","author":"EM Shevach","year":"2009","journal-title":"Immunity"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/hep.26583","article-title":"Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis","volume":"59","author":"CR Grant","year":"2014","journal-title":"Hepatology (Baltimore, Md)"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jhep.2004.03.008","article-title":"Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease","volume":"41","author":"MS Longhi","year":"2004","journal-title":"J Hepatol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jaut.2005.05.001","article-title":"Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis","volume":"25","author":"MS Longhi","year":"2005","journal-title":"J Autoimmun"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.4049\/jimmunol.176.7.4484","article-title":"Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis","volume":"176","author":"MS Longhi","year":"2006","journal-title":"J Immunol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jhep.2012.02.029","article-title":"FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency","volume":"57","author":"M Peiseler","year":"2012","journal-title":"Journal of hepatology"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.jhep.2014.05.034","article-title":"Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies","volume":"61","author":"R Taubert","year":"2014","journal-title":"Journal of hepatology"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1053\/j.gastro.2008.06.042","article-title":"Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling","volume":"135","author":"M Kido","year":"2008","journal-title":"Gastroenterology"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/hep.26023","article-title":"Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance","volume":"57","author":"P Lapierre","year":"2013","journal-title":"Hepatology (Baltimore, Md)"},{"key":"ref31","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","author":"L Stross","year":"2012","journal-title":"Hepatology (Baltimore, Md)"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1002\/hep.22559","article-title":"Local accumulation and activation of regulatory Foxp3(+) CD4 T(R) cells accompanies the appearance of activated CD8 T cells in the liver","volume":"48","author":"P Bochtler","year":"2008","journal-title":"Hepatology"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1053\/j.gastro.2010.05.075","article-title":"Effects and regulation of autoreactive CD8+ T cells in a transgenic mouse model of autoimmune hepatitis","volume":"139","author":"M Zierden","year":"2010","journal-title":"Gastroenterology"},{"key":"ref34","first-page":"3403","article-title":"Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs","volume":"118","author":"S L\u00fcth","year":"2008","journal-title":"The Journal of clinical investigation"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1084\/jem.20061852","article-title":"Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease","volume":"204","author":"K Lahl","year":"2007","journal-title":"J Exp Med"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0092-8674(94)90169-4","article-title":"T cell receptor antagonist peptides induce positive selection","volume":"76","author":"KA Hogquist","year":"1994","journal-title":"Cell"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1084\/jem.20120914","article-title":"Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells","volume":"209","author":"JM Weiss","year":"2012","journal-title":"J Exp Med"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.4049\/jimmunol.0904028","article-title":"Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells","volume":"184","author":"AM Thornton","year":"2010","journal-title":"J Immunol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1084\/jem.20131142","article-title":"CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets","volume":"211","author":"KS Smigiel","year":"2014","journal-title":"J Exp Med"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1046\/j.0818-9641.2001.01048.x","article-title":"Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'","volume":"80","author":"P Bertolino","year":"2002","journal-title":"Immunol Cell Biol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.autrev.2005.01.005","article-title":"T cell immunity in autoimmune hepatitis","volume":"4","author":"Y Ichiki","year":"2005","journal-title":"Autoimmun Rev"},{"key":"ref42","article-title":"Comparative analysis of portal hepatic infiltrating leukocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis","author":"DM Foureau","year":"2014","journal-title":"Clinical and experimental immunology"},{"key":"ref43","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","author":"RM Dunham","year":"2013","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.4049\/jimmunol.0901216","article-title":"Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver","volume":"184","author":"YH Oo","year":"2010","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"810939","DOI":"10.1155\/2011\/810939","article-title":"Toll-like receptors signaling contributes to immunopathogenesis of HBV infection","volume":"2011","author":"Y Kondo","year":"2011","journal-title":"Gastroenterology research and practice"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/hep.21498","article-title":"IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice","volume":"45","author":"A Erhardt","year":"2007","journal-title":"Hepatology (Baltimore, Md)"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"7221","DOI":"10.4049\/jimmunol.181.10.7221","article-title":"CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice","volume":"181","author":"H-X Wei","year":"2008","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature10664","article-title":"Response to self antigen imprints regulatory memory in tissues","volume":"480","author":"MD Rosenblum","year":"2011","journal-title":"Nature"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0143715","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T17:34:46Z","timestamp":1567359286000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0143715"}},"subtitle":[],"editor":[{"given":"Luis","family":"Graca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,11,24]]},"references-count":48,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2015,11,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0143715","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,24]]}}}