Format

Send to

Choose Destination
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

1
Department of Immunology, and.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
3
Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY.
4
Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY.
5
Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
6
Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, NJ.
7
Department of Pathology, Brigham and Women's Hospital, Boston, MA.
8
Program in Immunology and Immunotherapy Integrated Research Center, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
9
Department of Immunology, University of Washington, Seattle, WA; and.
10
Cell and Gene Therapy Program and Immunotherapy Integrated Research Center, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Abstract

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.

PMID:
30381375
PMCID:
PMC6307985
[Available on 2019-12-27]
DOI:
10.1182/blood-2017-10-812941
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center