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TIGIT safeguards liver regeneration through regulating natural killer cell‐hepatocyte crosstalk
Author(s) -
Bi Jiacheng,
Zheng Xiaodong,
Chen Yongyan,
Wei Haiming,
Sun Rui,
Tian Zhigang
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27245
Subject(s) - crosstalk , hepatocyte , liver regeneration , tigit , microbiology and biotechnology , natural killer cell , regeneration (biology) , chemistry , biology , immunology , immune system , t cell , biochemistry , cytotoxicity , engineering , in vitro , electronic engineering
Overactivation of innate immunity, particularly natural killer (NK) cells, is harmful to liver regeneration; however, the molecular mechanisms that limit NK cell overactivation during liver regeneration are still elusive. Here we show that a coinhibitory receptor, T cell Ig and ITIM domain (TIGIT), was selectively up‐regulated on NK cells, along with high expression of its ligand, poliovirus receptor (PVR/CD155), on hepatocytes during liver regeneration. The absence of TIGIT impaired liver regeneration in vivo , along with overactivation of NK cells and higher NK‐derived interferon‐gamma (IFN‐γ) production. We also show that both depletion of NK cells and deficiency of IFN‐γ, but not deficiency of RAG1, rescued impaired liver regeneration caused by the absence of TIGIT. Adoptive transfer of Tigit –/– NK cells into NK‐deficient Nfil3 –/– mice sufficiently led to impairment of liver regeneration. On the other hand, silencing PVR in hepatocytes rescued impaired liver regeneration caused by TIGIT deficiency in vivo , while blockade of TIGIT in NK‐hepatocyte coculture increased IFN‐γ production by NK cells in vitro . Conclusion : TIGIT is a safeguard molecule to improve liver regeneration through negatively regulating NK‐hepatocyte crosstalk. This finding suggests a novel mechanism of NK cell self‐tolerance towards regenerative hyperplasia of the host. (H epatology 2014;60:1389–1398)