{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:19:09Z","timestamp":1790882349522,"version":"4.1.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1126,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4posCD25pos regulatory T cells (T-regs). Galectin-9 (Gal9), a \u03b2-galactosidase\u2013binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and\/or Tim-3 on CD4 effector cells. Circulating Gal9posCD4posCD25pos and Tim-3posCD4posCD25neg T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4posCD25neg T cells amenable to T-reg control, purified CD4posCD25negTim-3pos (Tim-3pos) and CD4posCD25negTim-3neg (Tim-3neg) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3pos cells within CD4posCD25neg cells and their T-betpos and RORCpos subsets were fewer and contained higher numbers of interferon-\u03b3 (IFN\u03b3)pos and interleukin (IL)-17pos cells than healthy subjects (HS). In AIH and HS, Tim-3pos cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3neg cells. In AIH, Gal9posT-regs were fewer and contained less FOXP3pos, IL-10pos, and transforming growth factor \u03b2pos and more IFN\u03b3pos and IL-17pos cells than HS. siRNA treatment of Gal-9pos T-regs drastically reduced T-reg ability to suppress CD4posCD25neg and Tim-3pos cell proliferation in AIH and HS. Tim-3pos cell percentage correlated inversely with aminotransferase and CD25negT-betpos cell values.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>\n                                 <jats:bold>: Reduced levels of Tim-3 on CD4posCD25neg effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing. (HEPATOLOGY 2012)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.25682","type":"journal-article","created":{"date-parts":[[2012,2,28]],"date-time":"2012-02-28T05:17:58Z","timestamp":1330406278000},"page":"677-686","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":131,"title":["The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9\/tim-3 pathway"],"prefix":"10.1097","volume":"56","author":[{"given":"Rodrigo","family":"Liberal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte R.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth S.","family":"Holder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgina","family":"Mieli-Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Serena","family":"Longhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-31-20241201","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.jaut.2009.08.010","article-title":"Aetiopathogenesis of autoimmune hepatitis.","volume":"34","author":"Longhi","year":"2010","journal-title":"J Autoimmun"},{"key":"R2-31-20241201","doi-asserted-by":"crossref","first-page":"541547","DOI":"10.1002\/hep.510250308","article-title":"Autoimmune hepatitis in childhood: a 20year experience.","volume":"25","author":"Gregorio","year":"1997","journal-title":"HEPATOLOGY"},{"key":"R3-31-20241201","doi-asserted-by":"crossref","first-page":"868882","DOI":"10.1053\/j.gastro.2005.12.020","article-title":"Polyclonal Tcell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.","volume":"130","author":"Ma","year":"2006","journal-title":"Gastroenterology"},{"key":"R4-31-20241201","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1016\/j.jhep.2004.03.008","article-title":"Impairment of CD4()CD25() regulatory Tcells in autoimmune liver disease.","volume":"41","author":"Longhi","year":"2004","journal-title":"J Hepatol"},{"key":"R5-31-20241201","doi-asserted-by":"crossref","first-page":"44844491","DOI":"10.4049\/jimmunol.176.7.4484","article-title":"Functional study of CD4CD25 regulatory T cells in health and autoimmune hepatitis.","volume":"176","author":"Longhi","year":"2006","journal-title":"J Immunol"},{"key":"R6-31-20241201","doi-asserted-by":"crossref","first-page":"9991007","DOI":"10.1002\/hep.23792","article-title":"A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis.","volume":"52","author":"Ferri","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R7-31-20241201","doi-asserted-by":"crossref","first-page":"531562","DOI":"10.1146\/annurev.immunol.21.120601.141122","article-title":"Naturally arising CD4 regulatory T cells for immunologic selftolerance and negative control of immune responses.","volume":"22","author":"Sakaguchi","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"R8-31-20241201","doi-asserted-by":"crossref","first-page":"775787","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance.","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"R9-31-20241201","doi-asserted-by":"crossref","first-page":"536547","DOI":"10.1002\/hep.24039","article-title":"Autoantigenspecific regulatory T cells, a potential tool for immunetolerance reconstitution in type2 autoimmune hepatitis.","volume":"53","author":"Longhi","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R10-31-20241201","doi-asserted-by":"crossref","first-page":"665669","DOI":"10.1016\/j.coi.2006.09.009","article-title":"TIM3 in autoimmunity.","volume":"18","author":"Anderson","year":"2006","journal-title":"Curr Opin Immunol"},{"key":"R11-31-20241201","first-page":"259270","article-title":"The costimulatory role of TIM molecules.","volume":"229","author":"RodriguezManzanet","year":"2009","journal-title":"Immunol Rev"},{"key":"R12-31-20241201","doi-asserted-by":"crossref","first-page":"12451252","DOI":"10.1038\/ni1271","article-title":"The Tim3 ligand galectin9 negatively regulates T helper type 1 immunity.","volume":"6","author":"Zhu","year":"2005","journal-title":"Nat Immunol"},{"key":"R13-31-20241201","first-page":"10931101","article-title":"Tim3 inhibits T helper type 1mediated auto and alloimmune responses and promotes immunological tolerance.","volume":"4","author":"SanchezFueyo","year":"2003","journal-title":"Nat Immunol"},{"key":"R14-31-20241201","doi-asserted-by":"crossref","first-page":"11021110","DOI":"10.1038\/ni988","article-title":"Interaction of Tim3 and Tim3 ligand regulates T helper type 1 responses and induction of peripheral tolerance.","volume":"4","author":"Sabatos","year":"2003","journal-title":"Nat Immunol"},{"key":"R15-31-20241201","doi-asserted-by":"crossref","first-page":"14131418","DOI":"10.1084\/jem.20060210","article-title":"Dysregulated T cell expression of TIM3 in multiple sclerosis.","volume":"203","author":"Koguchi","year":"2006","journal-title":"J Exp Med"},{"key":"R16-31-20241201","doi-asserted-by":"crossref","first-page":"44094414","DOI":"10.4049\/jimmunol.180.7.4409","article-title":"Lack of TIM3 Immunoregulation in multiple sclerosis.","volume":"180","author":"Yang","year":"2008","journal-title":"J Immunol"},{"key":"R17-31-20241201","first-page":"91229130","article-title":"Negative immune regulator Tim3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4 and CD8 T cells.","volume":"83","author":"GoldenMason","year":"2009","journal-title":"J Virol"},{"key":"R18-31-20241201","doi-asserted-by":"crossref","first-page":"45464557","DOI":"10.1172\/JCI43127","article-title":"Tim3 expression on PD1 HCVspecific human CTLs is associated with viral persistence, and its blockade restores hepatocytedirected in vitro cytotoxicity.","volume":"120","author":"McMahan","year":"2010","journal-title":"J Clin Invest"},{"key":"R19-31-20241201","doi-asserted-by":"crossref","first-page":"544553","DOI":"10.1053\/jhep.2001.22131","article-title":"Autoimmune hepatitissclerosing cholangitis overlap syndrome in childhood: a 16year prospective study.","volume":"33","author":"Gregorio","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R20-31-20241201","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.1016\/j.jaut.2005.05.001","article-title":"Effect of CD4 CD25 regulatory Tcells on CD8 Tcell function in patients with autoimmune hepatitis.","volume":"25","author":"Longhi","year":"2005","journal-title":"J Autoimmun"},{"key":"R21-31-20241201","doi-asserted-by":"crossref","first-page":"130142","DOI":"10.1002\/hep.22914","article-title":"Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory Tcells.","volume":"50","author":"Longhi","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R22-31-20241201","doi-asserted-by":"crossref","first-page":"581591","DOI":"10.1002\/hep.22071","article-title":"Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis.","volume":"47","author":"Longhi","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R23-31-20241201","doi-asserted-by":"crossref","first-page":"36313636","DOI":"10.4049\/jimmunol.170.7.3631","article-title":"Galectin9 induces apoptosis through the calciumcalpaincaspase1 pathway.","volume":"170","author":"Kashio","year":"2003","journal-title":"J Immunol"},{"key":"R24-31-20241201","doi-asserted-by":"crossref","first-page":"859866","DOI":"10.1002\/eji.200939842","article-title":"Tbet, a Th1 transcription factor regulates the expression of Tim3.","volume":"40","author":"Anderson","year":"2010","journal-title":"Eur J Immunol"},{"key":"R25-31-20241201","doi-asserted-by":"crossref","first-page":"14111420","DOI":"10.4049\/jimmunol.176.3.1411","article-title":"Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cellmediated immune response.","volume":"176","author":"Geng","year":"2006","journal-title":"J Immunol"},{"key":"R26-31-20241201","doi-asserted-by":"crossref","first-page":"13171326","DOI":"10.1172\/JCI25308","article-title":"Anti-IL23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.","volume":"116","author":"Chen","year":"2006","journal-title":"J Clin Invest"},{"key":"R27-31-20241201","doi-asserted-by":"crossref","first-page":"24922501","DOI":"10.1002\/eji.200939274","article-title":"TIM3 is expressed on activated human CD4 T cells and regulates Th1 and Th17 cytokines.","volume":"39","author":"Hastings","year":"2009","journal-title":"Eur J Immunol"},{"key":"R28-31-20241201","doi-asserted-by":"crossref","first-page":"7888","DOI":"10.1016\/j.clim.2008.01.006","article-title":"Galectin9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis.","volume":"127","author":"Seki","year":"2008","journal-title":"Clin Immunol"},{"key":"R29-31-20241201","doi-asserted-by":"crossref","first-page":"e9504","DOI":"10.1371\/journal.pone.0009504","article-title":"A crucial role for Kupffer cellderived galectin9 in regulation of T cell immunity in hepatitis C infection.","volume":"5","author":"Mengshol","year":"2010","journal-title":"PLoS One"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.25682","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201208000-00031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T14:05:43Z","timestamp":1733061943000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201208000-00031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.25682","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2012,8]]}}}