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INFLAMMATION/IMMUNITY/MEDIATORS

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

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

Submitted 31 July 2008 ; accepted in final form 3 March 2009

Helper T cells are known to mediate hepatic ischemia/reperfusion (I/R) injury. However, the precise mechanisms and subsets of CD4⁺ T cells that contribute to this injury are still controversial. Therefore, we sought to determine the contributions of different CD4⁺ T cell subsets during hepatic I/R injury. Wild-type, OT-II, or T cell receptor (TCR)--deficient mice were subjected to 90 min of partial hepatic ischemia followed by 8 h of reperfusion. Additionally, wild-type mice were pretreated with anti-CD1d, -NK1.1, or -IL-2R- antibodies before I/R injury. OT-II mice had diminished liver injury compared with wild-type mice, implicating that antigen-dependent activation of CD4⁺ T cells through TCRs is involved in hepatic I/R injury. TCR- knockout mice had decreased hepatic neutrophil accumulation, suggesting that T cells regulate neutrophil recruitment. We found that natural killer T (NKT) cells, but not NK cells, contribute to hepatic I/R injury via CD1d-dependent activation of their TCRs, as depletion of NKT cells by anti-CD1d antibody or depletion of both NKT cells and NK cells by anti-NK1.1 attenuated liver injury. Although regulatory T cells (Treg) are known to suppress T cell-dependent inflammation, depletion of Treg cells had little effect on hepatic I/R injury. The data suggest that antigen-dependent activation of CD4⁺ T cells contributes to hepatic I/R injury. Among the subsets of CD4⁺ T cells, it appears that T cells contribute to neutrophil recruitment and that NKT cells directly injure the liver. In contrast, NK cells and Treg have little effects on hepatic I/R injury.

T cell receptor; T cell; natural killer T cell; OT-II