CD4⁺ T Cell NRF2 Signaling Improves Liver Transplantation Outcomes by Modulating T Cell Activation and...

Innate and adaptive immune responses regulate hepatic ischemia-reperfusion injury (IRI) in orthotopic liver transplantation (OLT). While the mechanism of how nuclear factor erythroid 2-related factor 2 (NRF2) plays a role in liver IRI has been studied, the contribution of T cell-specific NRF2 in OLT remains unknown. In the current translational study, we investigated whether and how CD4⁺ T cell-specific NRF2 signaling affects liver transplant outcomes in mice and humans. In the experimental arm, cold-stored (4°C/18 h) wild-type (WT) mouse livers transplanted to NRF2-deficient (NRF2-knockout [NRF2-KO]) recipients experienced greater hepatocellular damage than those in Nrf2-proficient (WT) counterparts, evidenced by Suzuki's histological scores, frequency of TdT-mediated dUTP nick end labeling (TUNEL)⁺ cells, and elevated serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels. In vitro studies showed that NRF2 signaling suppressed CD4⁺ T cell differentiation to a proinflammatory phenotype (Th1, Th17) while promoting the regulatory (Foxp3⁺) T cell lineage. Furthermore, OLT injury deteriorated in immune-compromised RAG2-KO test recipients repopulated with CD4⁺ T cells from NRF2-KO compared with WT donor mice. In the clinical arm of 45 human liver transplant patients, the perioperative increase of NRF2 expression in donor livers negatively regulated innate and adaptive immune activation, resulting in reduced hepatocellular injury in NRF2-proficient OLT. CD4⁺ T cell population expressing NRF2 attenuated ischemia and reperfusion (IR)-triggered hepatocellular damage in a clinically relevant mouse model of extended donor liver cold storage, followed by OLT, whereas the perioperative increase of NRF2 expression reduced hepatic injury in human liver transplant recipients. Thus, CD4⁺ T cell NRF2 may be a novel cytoprotective sentinel against IR stress in OLT recipients. Antioxid. Redox Signal. 38, 670-683.