title: In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression.
abstract: Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory T-cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4(+) CD25(+) or CD4(+) CD25(high) cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4(+) CD25(+) CD127(-) Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona-fide Tregs produce less interleukin (IL)-10 and are impaired in their ability to suppress CD4(+) CD25(-) target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL-10 secretion. Decreased IL-10 production by Tregs in AILD is linked to poor responsiveness to IL-2 and phospho signal transducer and activator of transcription 5 up-regulation.
  
  
  CONCLUSIONS
  Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL-10 production, resulting from low Treg responsiveness to IL-2, contributes to Treg functional impairment.
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.|Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Liberal
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Grant
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Beth S
authors.initials: BS
authors.lastname: Holder
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Cardone
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Martinez-Llordella
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Heneghan
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.|Pediatric Liver, GI & Nutrition Center, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Center for Transplantation, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Longhi
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015704:CD4 Antigens / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D015209:Cholangitis, Sclerosing / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D005434:Flow Cytometry; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D015999:Multivariate Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D016753:Interleukin-10