Regulatory T cells (Tregs) have a profound ability to control immune responses. A majority of Tregs are derived from the thymus; yet a substantial Treg fraction is derived from the periphery. The liver seems to be an important source of peripherally derived Tregs. Indeed, the liver's well-known ability to induce immune tolerance is at least partly based on hepatic Treg generation. With recently developed tools to deliver antigens to tolerance-inducing liver cells, it is now possible to harness liver-derived Tregs for specific control of unwanted immune responses. Indeed, the selective delivery of autoantigens to liver sinusoidal endothelial cells could induce autoantigen-specific Tregs in vivo, providing effective treatment of autoimmune disease. Owing to the fundamental role Tregs play in controlling immune responses, an impairment of Tregs seems to be a plausible explanation for the development of autoimmune diseases, for example, in the liver. However, the actual role of Treg impairment in autoimmune liver diseases, such as autoimmune hepatitis (AIH), remains controversial. Major obstacles for clarifying the role of Tregs in autoimmune liver diseases are related to the difficulty to identify human Tregs unambiguously and to the difficulty to identify those Tregs and effector T cells that specifically recognize disease-driving autoantigens. However, even if AIH turned out to be a disease that is not driven by Treg impairment, Treg-based therapies for autoimmune liver diseases might still be effective, provided the Tregs for therapeutic use recognize the relevant antigens.

Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell 2008;133:775-787.
Wing K, Sakaguchi S: Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 2010;11:7-13.
Jonuleit H, Schmitt E: The regulatory T cell family: distinct subsets and their interrelations. J Immunol 2003;171:6323-6327.
Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF: Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 2013;14:307-308.
Shevach EM: Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009;30:636-645.
Curotto de Lafaille MA, Lafaille JJ: Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009;30:626-635.
Liu W, et al: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-1711.
Peiseler M, Sebode M, Schramm C, Herkel J: Reply to ‘T regulatory cell number and function: the autoimmune traits in liver diseases'. J Hepatol 2012;57:1399-1400.
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG: Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013;19:739-746.
Racanelli V, Rehermann B: The liver as an immunological organ. Hepatology 2006;43(2 suppl 1):S54-S62.
Carambia A, Herkel J: CD4 T cells in hepatic immune tolerance. J Autoimmun 2010;34:23-28.
Thomson AW, Knolle PA: Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010;10:753-766.
Lüth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C, Brück W, Wraith DC, Herkel J, Lohse AW: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 2008;118:3403-3410.
Carambia A, Freund B, Schwinge D, Heine M, Laschtowitz A, Huber S, Wraith DC, Korn T, Schramm C, Lohse AW, Heeren J, Herkel J: TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells. J Hepatol 2014;61:594-599.
LoDuca PA, Hoffman BE, Herzog RW: Hepatic gene transfer as a means of tolerance induction to transgene products. Curr Gene Ther 2009;9:104-114.
Sack BK, Herzog RW, Terhorst C, Markusic DM: Development of gene transfer for induction of antigen-specific tolerance. Mol Ther Methods Clin Dev 2014;1:14013.
Carambia A, Freund B, Schwinge D, Bruns OT, Salmen SC, Ittrich H, Reimer R, Heine M, Huber S, Waurisch C, Eychmüller A, Wraith DC, Korn T, Nielsen P, Weller H, Schramm C, Lüth S, Lohse AW, Heeren J, Herkel J: Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J Hepatol 2015;62:1349-1356.
Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P, Martin C, van Rooijen N, Ochando JC, Randolph GJ, Luedde T, Ginhoux F, Kurts C, Trautwein C, Tacke F: Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 2015;62:279-291.
Hirschfield GM, Karlsen TH, Lindor KD, Adams DH: Primary sclerosing cholangitis. Lancet 2013;382:1587-1599.
Selmi C, Bowlus CL, Gershwin ME, Coppel RL: Primary biliary cirrhosis. Lancet 2011;377:1600-1609.
Heneghan MA, Yeoman AD, Verma S, Smith AD, Longhi MS: Autoimmune hepatitis. Lancet 2013;382:1433-1444.
Czaja AJ, Manns MP: Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology 2010;139:58-72.e4.
Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D: Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41:31-37.
Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, Ma Y: Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006;176:4484-4491.
Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, Hussain MJ, Ma Y, Lenzi M, Mieli-Vergani G, Bianchi FB, Vergani D, Muratori L: A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 2010;52:999-1007.
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA: CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-1253.
Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, Baron U, Olek S, Wiegard C, Lohse AW, Weiler-Normann C, Schramm C, Herkel J: FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 2012;57:125-132.
Peiseler M, Sebode M, Schramm C, Herkel J: Reply to: ‘regulatory T cell defects in autoimmune hepatitis'. J Hepatol 2012;57:1155-1156.
Sebode M, Peiseler M, Weiler-Normann C, Schramm C, Lohse AW, Herkel J: Phenotypic alterations of regulatory T cells in autoimmune hepatitis: causal or associated with treatment and remission? Hepatology 2015;61:736-737.
Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B: Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693-1700.
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-1711.
Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, Hamann A, Loddenkemper C, Stein H, Volk HD, Hoffmüller U, Grützkau A, Mustea A, Huehn J, Scheibenbogen C, Olek S: Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res 2009;69:599-608.
Taubert R, Hardtke-Wolenski M, Noyan F, Wilms A, Baumann AK, Schlue J, Olek S, Falk CS, Manns MP, Jaeckel E: Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J Hepatol 2014;61:1106-1114.
Sebode M, Peiseler M, Franke B, Schwinge D, Schoknecht T, Wortmann F, Quaas A, Petersen BS, Ellinghaus E, Baron U, Olek S, Wiegard C, Weiler-Normann C, Lohse AW, Herkel J, Schramm C: Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms. J Hepatol 2014;60:1010-1016.
Longhi MS, Hussain MJ, Kwok WW, Mieli-Vergani G, Ma Y, Vergani D: Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 2011;53:536-547.
Rosenblum MD, Gratz IK, Paw JS, Abbas AK: Treating human autoimmunity: current practice and future prospects. Sci Transl Med 2012;4:125sr1.
Leslie M: Immunology. Regulatory T cells get their chance to shine. Science 2011;332:1020-1021.
Longhi MS, Liberal R, Holder B, Robson SC, Ma Y, Mieli-Vergani G, Vergani D: Inhibition of interleukin-17 promotes differentiation of CD25 cells into stable T regulatory cells in patients with autoimmune hepatitis. Gastroenterology 2012;142:1526-1535.e6.
Lapierre P, Béland K, Yang R, Alvarez F: Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology 2013;57:217-227.
Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM, Shetty S, Harki J, Shaw JC, Eksteen B, Hubscher SG, Walker LS, Adams DH: Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010;184:2886-2898.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.