Liver ischemia-reperfusion injury (IRI) after liver transplantation is a major cause of delayed graft function. We previously demonstrated that the specific expressions of CD137 on NK cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the CXCR2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. In contrast, the present study demonstrated that liver IRI was more severe in CD137-deficient than in wild-type (WT) mice. Transfer of WT NK cells into CD137-deficient mice ameliorated liver IRI. Further analysis showed that CD137 signaling in NK cells resulted in production of high levels of IL-10. Transfer of IL-10-producing NK cells expanded by agonistic anti-CD137 monoclonal antibody was effective in inhibiting liver IRI and neutralization of IL-10 abrogated the protective activity of these NK cells. Our findings identify a previously unrecognized function of CD137 signaling in NK cells. The CD137 signaling pathway in NK cells may therefore represent a good target for blocking liver IRI.

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