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Blood. 2018 Dec 27;132(26):2763-2774. doi: 10.1182/blood-2017-10-812941. Epub 2018 Oct 31.

Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.

Author information

Department of Immunology, and.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY.
Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY.
Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, NJ.
Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Program in Immunology and Immunotherapy Integrated Research Center, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Department of Immunology, University of Washington, Seattle, WA; and.
Cell and Gene Therapy Program and Immunotherapy Integrated Research Center, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.


Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for 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 for 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 characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.

[Available on 2019-12-27]
[Indexed for MEDLINE]

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