Invariant natural killer T cells suppress the neutrophil inflammatory response in a mouse model of cholestatic liver damage.
OBJECTIVE
NK1.1(+) TCRalphabeta(int) CD1-restricted T (NKT) cells are a unique subset of T lymphocytes that are believed to have an immunoregulatory role in a wide range of diseases. Most mouse NKT cells express a T-cell receptor that contains an invariant Valpha14Jalpha18 chain and recognizes antigenic glycolipids presented in association with major histocompatibility complex class Ib (CD1d) molecules. These invariant NKT (iNKT) cells have been implicated in cholestatic liver injury.


METHODS
We examined the role of iNKT cells in liver injury associated with biliary obstruction in mice with ligations of the common bile duct.


RESULTS
The number of activated iNKT cells increased markedly in the livers of mice following bile duct ligation. Plasma alanine aminotransferase levels, an indicator of liver injury, were significantly higher in iNKT cell-deficient (Jalpha18(-/-)) mice compared with wild-type mice following bile duct ligation. Photo image analysis of histologic sections confirmed that more damage was present in the livers of Jalpha18(-/-) mice; liver damage correlated with increases in keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) production as well as neutrophil sequestration. Liver injury was significantly reduced in Jalpha18(-/-) mice treated with anti-KC and anti-MIP-2 or rendered neutrophil deficient before bile duct ligation. Similarly, Jalpha18(-/-) mice that were injected with iNKT cells before bile duct ligation exhibited significant decreases in neutrophil accumulation and liver damage.


CONCLUSIONS
These data document the role of iNKT cells in suppressing the neutrophil proinflammatory response and neutrophil-dependent cholestatic liver damage.
Wintermeyer
Philip
P
Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Cheng
Chao-Wen
CW
Gehring
Stephan
S
Hoffman
Beth L
BL
Holub
Martin
M
Brossay
Laurent
L
Gregory
Stephen H
SH
D019264:Adoptive Transfer; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D001651:Cholestasis, Extrahepatic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D003135:Common Bile Duct; D004195:Disease Models, Animal; D005260:Female; D006505:Hepatitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007108:Immune Tolerance / Q000276:immunology*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000637:transplantation*; D009504:Neutrophils / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms
D018925:Chemokines