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

Abstract

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.

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…We have previously shown that ␥␦ T cells are recruited to the liver within 1 h of reperfusion, a time that precedes the recruitment of neutrophils (4). In the present study, we found that hepatic neutrophil recruitment was suppressed in TCR-␦-deficient mice after I/R compared with wild-type mice.…”

“…Although the precise mechanisms of these effects are unclear, we speculate that CD4 or NKT cell-specific cytokines could directly or indirectly regulate neutrophil function such that the same degree of liver injury could be induced by a lower number of neutrophils with a higher state of activation. This concept was validated in our previous studies, which demonstrated that neutrophils isolated from the livers of CD4 knockout mice had a higher oxidative burst than those from wild-type mice (4).…”

“…These studies demonstrated that depletion or deficiency of CD4 ϩ T cells attenuates liver injury, hepatic neutrophil infiltration, and platelet-endothelial cell interaction. We have also reported that CD4 ϩ T cells are an important regulator of hepatic neutrophil recruitment during I/R via their release of IL-17 (4).…”

“…Accumulating data suggest that CD4 ϩ T cells mediate liver neutrophil recruitment and liver injury (4,20,44). However, the precise mechanisms by which subsets of T cells contribute to hepatic I/R injury are not fully understood.…”

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

“…24,25 Recently, T cells, particularly of the CD4 phenotype, have been revealed as the key players regulating KC and neutrophil function. 13,26 However, the mechanism of T cell function in IRI remains unclear. We have shown that the induction of T cell-targeted chemokine CXCL10 correlated with the development of liver inflammation in a murine nontransplant IRI model.…”