Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus.
Hepatitis B virus (HBV) is a hepadnavirus that is a major cause of acute and chronic hepatitis in humans. Hepatitis B viral infection itself is noncytopathic, and it is the immune response to the viral antigens that is thought to be responsible for hepatic pathology. Previously, we developed a transgenic mouse model of primary HBV infection and demonstrated that the acute liver injury is mediated by nonclassical natural killer (NK)T cells, which are CD1d-restricted, but nonreactive to alpha-GalCer. We now demonstrate a role for NKG2D and its ligands in this nonclassical NKT cell-mediated immune response to hepatitis B virus and in the subsequent acute hepatitis that ensues. Surface expression of NKG2D and one of its ligands (retinoic acid early inducible-1 or RAE-1) are modulated in an HBV-dependent manner. Furthermore, blockade of an NKG2D-ligand interaction completely prevents the HBV- and CD1d-dependent, nonclassical NKT cell-mediated acute hepatitis and liver injury. This study has major implications for understanding activation of NKT cells and identifies a potential therapeutic target in treating hepatitis B viral infection.
Vilarinho
Sílvia
S
Department of Medicine, Liver Center, University of California, San Francisco, CA 94143, USA.
Ogasawara
Kouetsu
K
Nishimura
Stephen
S
Lanier
Lewis L
LL
Baron
Jody L
JL
D000818:Animals; D002460:Cell Line; D006509:Hepatitis B / Q000517:prevention & control*; D006515:Hepatitis B virus / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D055607:Receptors, Natural Killer Cell; D014779:Virus Replication
C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell