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Liver-resident NK cells suppress autoimmune cholangitis and limit the proliferation of CD4+ T cells

Cellular & Molecular Immunology (2019) | Download Citation

Abstract

Liver-resident NK cells are distinct from conventional NK cells and play an important role in the maintenance of liver homeostasis. How liver-resident NK cells participate in autoimmune cholangitis remains unclear. Here, we extensively investigated the impact of NK cells in the pathogenesis of autoimmune cholangitis utilizing the well-established dnTGFβRII cholangitis model, NK cell-deficient (Nfil3−/−) mice, adoptive transfer and in vivo antibody-mediated NK cell depletion. Our data demonstrated that disease progression was associated with a significantly reduced frequency of hepatic NK cells. Depletion of NK cells resulted in exacerbated autoimmune cholangitis in dnTGFβRII mice. We further confirmed that the DX5CD11chi liver-resident NK cell subset colocalized with CD4+ T cells and inhibited CD4+ T cell proliferation. Gene expression microarray analysis demonstrated that liver-resident NK cells had a distinct gene expression pattern consisting of the increased expression of genes involved in negative regulatory functions in the context of the inflammatory microenvironment.

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Acknowledgements

This study was supported by the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2017ZT07S054), the National Natural Science Foundation of China (81601416, 81430034, 91542123), the National Key R&D Program of China (2017YFA0205600) and a National Institutes of Health grant (DK090019).

Author information

Author notes

  1. These authors contributed equally: Zhi-Bin Zhao, Fang-Ting Lu, Hong-Di Ma.

Affiliations

  1. Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China

    • Zhi-Bin Zhao
    • , Jie Long
    • , Jie Cao
    •  & Zhe-Xiong Lian
  2. Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China

    • Zhi-Bin Zhao
    • , Jie Long
    •  & Zhe-Xiong Lian
  3. Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China

    • Zhi-Bin Zhao
    • , Hong-Di Ma
    • , Yin-Hu Wang
    • , Wei Yang
    • , Jie Long
    • , Zhigang Tian
    •  & Zhe-Xiong Lian
  4. Center for Reproductive Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China

    • Fang-Ting Lu
  5. Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    • Qi Miao
  6. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA

    • Weici Zhang
    •  & M. Eric Gershwin
  7. Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH, 45267, USA

    • William M. Ridgway

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The authors declare no competing interests.

Corresponding authors

Correspondence to Jie Cao or M. Eric Gershwin or Zhe-Xiong Lian.

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DOI

https://doi.org/10.1038/s41423-019-0199-z