Clonality, activated antigen-specific CD8+ T cells, and development of autoimmune cholangitis in dnTGFβRII mice

Authors

  • Kazuhito Kawata,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
    2. Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
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  • Guo-Xiang Yang,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Yugo Ando,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Hajime Tanaka,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Weici Zhang,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Yoshimasa Kobayashi,

    1. Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
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  • Koichi Tsuneyama,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
    2. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
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  • Patrick S.C. Leung,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Zhe-Xiong Lian,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
    2. Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China
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  • William M. Ridgway,

    1. Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Aftab A. Ansari,

    1. Department of Pathology, Emory University School of Medicine, Atlanta, GA
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  • Xiao-Song He,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • M. Eric Gershwin

    Corresponding author
    • Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
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  • Potential conflict of interest: Nothing to report.

  • Supported by National Institutes of Health grant DK090019.

Address reprint requests to: M. Eric Gershwin, M.D., Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ucdavis.edu; fax: 530-752-4669.

Abstract

There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8+ T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1−/− recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8+ T cells or due to the abnormal TGFβR environment within which CD8+ T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1−/−, OT-II/Rag1−/− mice and in addition generated OT-I/dnTGFβRII/Rag1−/−, and OT-II/dnTGFβRII/Rag1−/− mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8+ or CD4+ T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1−/− mice and/or OT-II/dnTGFβRII/Rag1−/− mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8+ T cells from dnTGFβRII mice but not CD8+ T cells from OT-I/Rag1−/− mice or from OT-I/dnTGFβRII/Rag1−/− mice transferred disease. These data were not secondary to an absence of CD4+ T cell help since a combination of CD8+ T cells from OT-I/dnTGFβRII/Rag1−/− and CD4+ T cells from OT II/dnTGFβRII/Rag1−/− or CD8+ T cells from OT-I/dnTGFβRII/Rag1−/− with CD4+ T cells from OT-II/Rag1−/− mice failed to transfer disease. Conclusion: Defective TGFβRII signaling, in addition to clonal CD8+ T cells that target biliary cells, are required for induction of autoimmune cholangitis. (Hepatology 2013;53:1094–1104)

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