Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion.
Hepatic ischemia-reperfusion results in an acute inflammatory response culminating in the recruitment of activated neutrophils that directly injure hepatocytes. Recent evidence suggests that CD4+ lymphocytes may regulate this neutrophil-dependent injury, but the mechanisms by which this occurs remain to be elucidated. In the present study, we sought to determine the type of CD4+ lymphocytes recruited to the liver after ischemia-reperfusion and the manner in which these cells regulated neutrophil recruitment and tissue injury. Wild-type and CD4 knockout (CD4-/-) mice were subjected to hepatic ischemia-reperfusion. CD4+ lymphocytes were recruited in the liver within 1 h of reperfusion and remained for at least 4 h. These cells were comprised of conventional (alphabetaTCR-expressing), unconventional (gammadeltaTCR-expressing), and natural killer T cells. CD4-/- mice were then used to determine the functional role of CD4+ lymphocytes in hepatic ischemia-reperfusion injury. Compared with wild-type mice, CD4-/- mice had significantly greater liver injury, yet far less neutrophil accumulation. Adoptive transfer of CD4+ lymphocytes to CD4-/- mice recapitulated the wild-type response. In wild-type mice, neutralization of interleukin (IL)-17, a cytokine released by activated CD4+ lymphocytes, significantly reduced neutrophil recruitment in association with suppression of MIP-2 expression. Finally, oxidative burst activity of liver-recruited neutrophils was higher in CD4-/- mice compared with those from wild-type mice. These data suggest that CD4+ lymphocytes are rapidly recruited to the liver after ischemia-reperfusion and facilitate subsequent neutrophil recruitment via an IL-17-dependent mechanism. However, these cells also appear to attenuate neutrophil activation. Thus the data suggest that CD4+ lymphocytes have dual, opposing roles in the hepatic inflammatory response to ischemia-reperfusion.
The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA.
Charles C
CC
Caldwell
Tomohisa
T
Okaya
Andre
A
Martignoni
Thomas
T
Husted
Rebecca
R
Schuster
Alex B
AB
Lentsch
D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D010641:Phenotype; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology*
D015704:CD4 Antigens