title: Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells.
abstract: Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGFβRII terminally differentiated (KLRG1(+)) CD8 T cells, a CD8 subset previously shown to be enriched in antigen specific cells during hepatic immune response to viral infections. We performed bone marrow chimera studies to assess whether dnTGFβRII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGFβRII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGFβRII single bone marrow chimerics. To define the protective B6 cell subset, we performed adoptive transfer studies, which showed that co-transfer of B6 Tregs prevented dnTGFβRII CD8 T cell mediated cholangitis. Treg mediated disease protection was associated with significantly decreased numbers of hepatic KLRG1(+) CD8 T cells. In contrast, co-transfer of dnTGFβRII Tregs offered no protection, and dnTGFβRII Treg cells were functionally defective in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In vitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGFβRII KLRG1(+) CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, and that an intrinsic T cell effector defect is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. These results have important implications for understanding the early pathogenesis of human PBC.
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45174, USA.
authors.forename: Wenting
authors.initials: W
authors.lastname: Huang
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45174, USA.
authors.forename: Kritika
authors.initials: K
authors.lastname: Kachapati
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45174, USA.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45174, USA.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45174, USA. Electronic address: ridgwawm@ucmail.uc.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D019070:Cell Lineage / Q000276:immunology; D002678:Chimera / Q000235:genetics / Q000276:immunology; D002761:Cholangitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D037181:Lectins, C-Type; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation
chemical_list: C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D018125:Receptors, Transforming Growth Factor beta
keywords: KLRG1(+) CD8 cells; Primary biliary cirrhosis; T regulatory cells