T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis

Authors

  • Jiacheng Bi,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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  • Qing Zhang,

    1. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Dan Liang,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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  • Lei Xiong,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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  • Haiming Wei,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Rui Sun,

    Corresponding author
    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
    • Address reprint requests to: Zhigang Tian, Ph.D., or Rui Sun, M.D., Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. E-mail: tzg@ustc.edu.cn or sunr@ustc.edu.cn; fax: +86-551-6360-0832.

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  • Zhigang Tian

    Corresponding author
    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
    • Address reprint requests to: Zhigang Tian, Ph.D., or Rui Sun, M.D., Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. E-mail: tzg@ustc.edu.cn or sunr@ustc.edu.cn; fax: +86-551-6360-0832.

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  • Potential conflict of interest: Nothing to report.

  • Supported by the Ministry of Science & Technology of China (973 Basic Science Project 2013CB530506, 2013CB944902) and the Natural Science Foundation of China (#31270954, #91029303, #31021061).

Abstract

Uncontrolled natural killer (NK) cell activation during the early response to acute viral infection can lead to severe immunopathology, and the mechanisms NK cells use to achieve self-tolerance in such contexts are currently unclear. Here, NK cells up-regulated a coinhibitory receptor, T-cell Ig and ITIM domain (TIGIT), during challenge with the viral double-stranded RNA (dsRNA) analog poly I:C. Blocking TIGIT by antibody treatment in vivo or a genetic deficiency in Tigit enhanced NK cell activation and aggravated liver injury in a poly I:C/D-GalN-induced model of acute fulminant hepatitis, suggesting that TIGIT is normally required for protecting against NK cell-mediated liver injury. Furthermore, adoptively transferring Tigit−/− NK cells into NK cell-deficient Nfil3−/− mice also resulted in elevated liver injury. Reconstituting Kupffer cell-depleted mice with poliovirus receptor (PVR/CD155, a TIGIT ligand)-silenced Kupffer cells led to aggravated liver injury in a TIGIT-dependent manner. Blocking TIGIT in an NK-Kupffer cell coculture in vitro enhanced NK cell activation and interferon-gamma (IFN-γ) production in a PVR-dependent manner. We also found that TIGIT was up-regulated selectively on NK cells and protected against liver injury in an acute adenovirus infection model in both an NK cell- and Kupffer cell-dependent manner. Knocking down PVR in Kupffer cells resulted in aggravated liver injury in response to adenovirus infection in a TIGIT-dependent manner. Conclusion: TIGIT negatively regulates NK-Kupffer cell crosstalk and alleviates liver injury in response to poly I:C/D-GalN challenge or acute adenovirus infection, suggesting a novel mechanism of NK cell self-tolerance in liver homeostasis during acute viral infection. (Hepatology 2014;59:1715–1725)

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