title: Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice.
abstract: Although it is known that activation of natural killer (NK) cells causes liver injury, the mechanisms underlying NK cell-induced killing of self-hepatocytes are not clear. We demonstrated that liver NK cells have cytotoxicity against normal syngeneic hepatocytes in mice. Polyinosinic-polycytidylic acid (poly I:C) treatment enhanced hepatocyte toxicity of liver NK cells but not that of spleen NK cells. Unlike NK cells in other tissues, approximately 30%-40% of liver NK cells constitutively express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). An in vitro NK cell cytotoxic assay revealed that hepatocyte toxicity of liver NK cells from both naïve and poly I:C-treated mice was inhibited partially by an anti-TRAIL monoclonal antibody (mAb) alone and completely by the combination with anti-Fas ligand (FasL) mAb and a perforin inhibitor, concanamycin A, indicating contribution of TRAIL to NK cell-mediated hepatocyte toxicity. The majority of TRAIL(+) NK cells lacked expression of Ly-49 inhibitory receptors recognizing self-major histocompatibility complex class I, indicating a propensity to targeting self-hepatocytes. Poly I:C treatment significantly upregulated the expression of Ly-49 receptors on TRAIL(-) NK cells. This might be a compensatory mechanism to protect self-class I-expressing cells from activated NK cell-mediated killing. However, such compensatory alteration was not seen at all in the TRAIL(+) NK cell fraction. Thus, liver TRAIL(+) NK cells have less capacity for self-recognition, and this might be involved in NK cell-dependent self-hepatocyte toxicity. In conclusion, our findings are consistent with a model in which TRAIL-expressing NK cells play a critical role in self-hepatocyte killing through poor recognition of MHC.
authors.affiliation: Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ochi
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsuta
authors.forename: Takashi
authors.initials: T
authors.lastname: Onoe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tokita
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: Kohei
authors.initials: K
authors.lastname: Ishiyama
authors.forename: Wendy
authors.initials: W
authors.lastname: Zhou
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Asahara
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D002450:Cell Communication / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D037181:Lectins, C-Type; D008099:Liver / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D055630:Receptors, NK Cell Lectin-Like; D013154:Spleen / Q000166:cytology / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D051017:Apoptosis Regulatory Proteins; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055630:Receptors, NK Cell Lectin-Like; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha