title: TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Bi
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D018920:Coculture Techniques; D022781:Hepatocytes / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011991:Receptors, Virus / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; C066100:poliovirus receptor; C064658:RAG-1 protein; D007371:Interferon-gamma