title: T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors: Jiacheng
authors: J
authors: Bi
authors: Qing
authors: Q
authors: Zhang
authors: Dan
authors: D
authors: Liang
authors: Lei
authors: L
authors: Xiong
authors: Haiming
authors: H
authors: Wei
authors: Rui
authors: R
authors: Sun
authors: Zhigang
authors: Z
authors: Tian
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000502:physiology; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology*; D007728:Kupffer Cells / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000502:physiology*; D011991:Receptors, Virus / Q000502:physiology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C116131:CD96 antigen; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; C066100:poliovirus receptor; D007371:Interferon-gamma; D011070:Poly I-C