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: Toshihiko Kawamura, Kazuyoshi Takeda, Hiroshi Kaneda, Hiroaki Matsumoto, Yoshihiro Hayakawa, David H Raulet, Yoshinori Ikarashi, Mitchell Kronenberg, Hideo Yagita, Katsuyuki Kinoshita, Toru Abo, Ko Okumura, Mark J Smyth
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 1 Pg. 250-8 (Jan 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19109156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Growth Inhibitors
• NK Cell Lectin-Like Receptor Subfamily C
• NK Cell Lectin-Like Receptor Subfamily D
• Receptors, Antigen, T-Cell
• Concanavalin A

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Cell Line
• Chemical and Drug Induced Liver Injury (immunology, metabolism, pathology)
• Concanavalin A (administration & dosage, toxicity)
• Down-Regulation (immunology)
• Growth Inhibitors (biosynthesis, genetics, physiology)
• Lymphocyte Activation (immunology)
• Melanoma, Experimental (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• NK Cell Lectin-Like Receptor Subfamily C (deficiency, genetics, immunology, physiology)
• NK Cell Lectin-Like Receptor Subfamily D (antagonists & inhibitors, physiology)
• Natural Killer T-Cells (immunology, metabolism, pathology)
• Receptors, Antigen, T-Cell (physiology)
• Signal Transduction (immunology)