{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:16Z","timestamp":1790660776198,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2009,1,1]],"date-time":"2009-01-01T00:00:00Z","timestamp":1230768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-\u03b3-, or IFN-\u03b3- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN-\u03b3 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\u2212 iNKT cells, which preferentially expressed CD94\/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1\u2212 iNKT cells. Moreover, Con A-induced and \u03b1-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.<\/jats:p>","DOI":"10.4049\/jimmunol.182.1.250","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:17:12Z","timestamp":1397848632000},"page":"250-258","source":"Crossref","is-referenced-by-count":36,"title":["NKG2A Inhibits Invariant NKT Cell Activation in Hepatic Injury"],"prefix":"10.1093","volume":"182","author":[{"given":"Toshihiko","family":"Kawamura","sequence":"first","affiliation":[{"name":"Department of Immunology, Niigata University School of Medicine , Niigata,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyoshi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Immunology"},{"name":"Cancer Immunology Program, Peter MacCallum Cancer Centre , East Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kaneda","sequence":"additional","affiliation":[{"name":"Department of Immunology"},{"name":"Department of Obstetric and Gynecology, Juntendo University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Immunology, Niigata University School of Medicine , Niigata,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Cancer Immunology Program, Peter MacCallum Cancer Centre , East Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H","family":"Raulet","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California , Berkeley, CA 94720"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Ikarashi","sequence":"additional","affiliation":[{"name":"Pharmacology Division, National Cancer Center Research Institute , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Kronenberg","sequence":"additional","affiliation":[{"name":"Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology , San Diego, CA 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Yagita","sequence":"additional","affiliation":[{"name":"Department of Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Obstetric and Gynecology, Juntendo University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Abo","sequence":"additional","affiliation":[{"name":"Department of Immunology, Niigata University School of Medicine , Niigata,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Smyth","sequence":"additional","affiliation":[{"name":"Cancer Immunology Program, Peter MacCallum Cancer Centre , East Melbourne, Victoria,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,1,1]]},"reference":[{"key":"2026012806232205300_R1","first-page":"557","article-title":"The unconventional lifestyle of NKT cells.","volume-title":"Nat. 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Immunol.","year":"1999"},{"key":"2026012806232205300_R43","first-page":"57","article-title":"Mechanism and biological significance of CD4-mediated cytotoxicity.","volume-title":"Immunol. Rev.","year":"1995"},{"key":"2026012806232205300_R44","first-page":"995","article-title":"Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia.","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012806232205300_R45","first-page":"11287","article-title":"Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4\u2212NK1.1\u2212 NKT cell population.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2008"},{"key":"2026012806232205300_R46","first-page":"821","article-title":"IL-17 family cytokines and the expanding diversity of effector T cell lineages.","volume-title":"Annu. Rev. 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