title: Age-associated augmentation of the synthetic ligand- mediated function of mouse NK1.1 ag(+) T cells: their cytokine production and hepatotoxicity in vivo and in vitro.
abstract: We recently reported that the direct antitumor effectors in the liver induced by alpha-galactosylceramide (alpha-GalCer) are NK cells that are activated by the IFN-gamma produced from NK1.1 Ag(+) T cells (NKT cells) specifically stimulated with alpha-GalCer, whereas NKT cells cause hepatocyte injury through the Fas-Fas ligand pathway. In the present study, we investigated how mouse age affects the alpha-GalCer-induced effect using young (6-wk-old), middle-aged (30-wk-old), and old (75-wk-old) mice. The serum IFN-gamma and IL-4 concentrations as well as alanine aminotransferase levels after the alpha-GalCer injection increased in an age-dependent manner. An alpha-GalCer injection also induced an age-dependent increase in the Fas ligand expression on liver NKT cells. Under the stimulus of alpha-GalCer in vitro, the liver mononuclear cells from old and middle-aged mice showed vigorous proliferation, remarkable antitumor cytotoxicity, and enhanced production of both IFN-gamma and IL-4 in comparison to those of young mice, all of which were mediated mainly by NK1.1(+) cells. Furthermore, liver mononuclear cells from old mice stimulated with alpha-GalCer showed a more potent Fas-Fas ligand-mediated cytotoxicity against primary cultured hepatocytes than did those from young mice. Most alpha-GalCer-injected old mice, but no young mice, died, while anti-IFN-gamma Ab pretreatment completely inhibited mouse mortality. However, alpha-GalCer-induced hepatic injury did not improve at all by anti-IFN-gamma Ab treatment, and the Fas-ligand expression of liver NKT cells did not change. Taken together, the synthetic ligand-mediated function of NKT cells is age-dependently up-regulated, and the produced IFN-gamma is responsible for alpha-GalCer-induced antitumor immunity and the mouse mortality, while hepatic injury was unexpectedly found to be independent of IFN-gamma.
authors.affiliation: Department of Microbiology, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Inui
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Shuri
authors.initials: S
authors.lastname: Ohkura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Habu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koike
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Motoki
authors.forename: Noritsugu
authors.initials: N
authors.lastname: Kuranaga
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukasawa
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
mesh_terms: D000375:Aging / Q000276:immunology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D000950:Antigens, Ly; D000954:Antigens, Surface; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D037181:Lectins, C-Type; D008024:Ligands; D008099:Liver / Q000276:immunology* / Q000293:injuries; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005699:Galactosylceramides; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D019014:fas Receptor; D007371:Interferon-gamma; D000410:Alanine Transaminase