title: NKG2A inhibits invariant NKT cell activation in hepatic injury.
abstract: Activation of invariant NKT (iNKT) cells in the liver is generally regarded as the critical step for Con A-induced hepatitis, and the role of NK cell receptors for iNKT cell activation is still controversial. In this study we show that blockade of the NKG2A-mediated inhibitory signal with antagonistic anti-NKG2A/C/E mAb (20d5) aggravated Con A-induced hepatitis in wild-type, Fas ligand (FasL)-mutant gld, and IL-4-deficient mice even with NK cell and CD8 T cell depletion, but not in perforin-, IFN-gamma-, or IFN-gamma- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN-gamma levels and perforin-dependent cytotoxicity of liver mononuclear cells following Con A injection, but not their FasL/Fas-dependent cytotoxicity. However, blockade of NKG2A-mediated signals during the cytotoxicity effector phase did not augment cytotoxic activity. Activated iNKT cells promptly disappeared after Con A injection, whereas NK1(-) iNKT cells, which preferentially expressed CD94/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1(-) iNKT cells. Moreover, Con A-induced and alpha-galactosylceramide-induced hepatic injury was very severe in CD94/NKG2A-deficient DBA/2J mice compared with CD94/NKG2A-intact DBA/2JJcl mice. Overall, these results indicated that a NKG2A-mediated signal negatively regulates iNKT cell activation and hepatic injury.
authors.affiliation: Department of Immunology, Niigata University School of Medicine, Niigata, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kawamura
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaneda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Toru
authors.initials: T
authors.lastname: Abo
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A / Q000008:administration & dosage / Q000633:toxicity; D015536:Down-Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000037:antagonists & inhibitors / Q000502:physiology; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D006131:Growth Inhibitors; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A