title: Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8+T cell activation.
abstract: CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFβRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag-/- mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8+T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8+T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8+T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Hong-Di
authors.initials: HD
authors.lastname: Ma
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Ma
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Qing-Zhi
authors.initials: QZ
authors.lastname: Liu
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Zhao
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Mu-Zi-Ying
authors.initials: MZ
authors.lastname: Liu
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Respiratory Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Gao
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA, USA.
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: feiyunyun2013@hotmail.com.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Fei
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China; Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China. Electronic address: zxlian1@ustc.edu.cn.
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007156:Immunologic Memory; D008024:Ligands; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000172:deficiency* / Q000378:metabolism
chemical_list: D016207:Cytokines; D008024:Ligands; D054367:Receptors, CXCR3
keywords: CD8+T cell gene expression profile; Interferon-gamma induced chemokines; KLRG1; Primary biliary cholangitis; T-bet