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16546

広告

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor well known for its role in regulating the cellular redox pathway. While there is mounting evidence suggesting a critical role of Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role of Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4 donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios donor regulatory T cells in the allograft, as well as defective upregulation of the gut homing receptor LPAM-1 on alloreactive CD8 T cells. Additionally, Nrf2 donor CD8 T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings not only characterized a previously unrecognized role of Nrf2 in T-cell function, but also revealed a novel therapeutic target to improve the outcomes of allo-HCT.
PMID: 30381375 [PubMed - as supplied by publisher]
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