@article{ab43a5fbca174e2085b997ac36ef0337,
title = "Nrf2 regulates CD41 T cell–induced acute graft-versus-host disease in mice",
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 CD41 donor T cells after allo-HCT. Allo-HCT recipients of Nrf22/2 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 Helios1 donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD81 T cells. Additionally, Nrf22/2 donor CD81 T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf22/2 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.",
author = "Tsai, {Jennifer J.} and Enrico Velardi and Yusuke Shono and Argyropoulos, {Kimon V.} and Holland, {Amanda M.} and Smith, {Odette M.} and Yim, {Nury L.} and Rao, {Uttam K.} and Kreines, {Fabiana M.} and Lieberman, {Sophie R.} and Young, {Lauren F.} and Amina Lazrak and Salma Youssef and Fu, {Ya Yuan} and Chen Liu and Cecilia Lezcano and Murphy, {George F.} and Na, {Il Kang} and Jenq, {Robert R.} and Hanash, {Alan M.} and Dudakov, {Jarrod A.} and {Van Den Brink}, {Marcel R.M.}",
note = "Funding Information: This work was supported by National Institutes of Health, National Cancer Institute (NCI) grants R01-CA228358-01 (M.R.M.v.d.B.) and R01-CA228308-01 (M.R.M.v.d.B.), Memorial Sloan Kettering Cancer Center Support Grant/Core grant P30 CA008748, and Project 4 of P01-CA023766-39 (M.R.M.v.d.B.) as well as National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL123340-04 (K. Cadwell), K08-HL115355 (A. M. Hanash), and R01-HL125571 (A. M. Hanash). Additional support was received from the National Institutes of Health, National Institute of Aging grant Project 2 of P01-AG052359-02 (M.R.M.v.d.B.) and by the Tri-Institutional Stem Cell Initiative award 2016-013 (S. Rafii). Support was also received from The Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSKCC and the European Union{\textquoteright}s Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement 602587. J.J.T. was supported by a Tumor Immunology Predoctoral Fellowship Training Grant from the Cancer Research Institute and the Dorris J. Hutchison Student Fellowship Award from Sloan Kettering Institute. E.V. is a 2018 Amy Strelzer Manasevit Research Scholar. A. M. Hanash also received research support from the Ludwig Center for Cancer Immunotherapy. Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology; all rights reserved.",
year = "2018",
month = dec,
day = "27",
doi = "10.1182/blood-2017-10-812941",
language = "English (US)",
volume = "132",
pages = "2763--2774",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "26",
}