title: CD4+CD25+ Regulatory T Cells Inhibit Natural Killer Cell Hepatocytotoxicity of Hepatitis B Virus Transgenic Mice via Membrane-Bound TGF-β and OX40.
abstract: CD4+CD25+ regulatory T cells (Tregs) are involved in the regulation of physiological and pathological hepatic immune responses, but the roles are not well explored in natural killer (NK) cell-mediated liver diseases. In this study, using the NK cell-mediated oversensitive liver injury model of hepatitis B virus transgenic (HBs-Tg) mice triggered by a low dose of concanavalin A, it was observed that an increased number of CD4+CD25+Foxp3+ Tregs were accumulated in the liver, along with the recovery of liver injury. Adoptive transfer of hepatic Tregs from HBs-Tg mice but not wild B6 mice could significantly attenuate the oversensitive liver injury via inhibiting liver accumulation and decreasing NK cell group 2D-mediated activation of NK cells in the recipient HBs-Tg mice. Furthermore, upregulated expression of membrane-bound TGF-β (mTGF-β) and OX40 on hepatic Tregs were demonstrated to account for inhibiting the NK cell-mediated hepatic injury in HBs-Tg mice through cell-cell contact, confirmed by antibody blockade and cell Transwell experiments in vivo and in vitro. Our findings for the first time indicated that CD4+CD25+ Tregs directly suppressed NK cell-mediated hepatocytotoxicity through mTGF-β and OX40/OX40L interaction in a cell-cell contact manner in HBV-associated liver disease.
authors.affiliation: Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, PR China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.forename: Xunyao
authors.initials: X
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002462:Cell Membrane / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; C527086:Klrk1 protein, mouse; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors; D003208:Concanavalin A