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Divergent functions of CD4⁺ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion

The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio

Submitted 17 May 2005 ; accepted in final form 1 July 2005

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 (TCR-expressing), unconventional (TCR-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.

liver injury; cell trafficking; neutrophils; T cells; interleukin-17

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