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

Item Type:	Article
Title:	Nrf2 regulates CD4(+) T cell-induced acute graft-versus-host disease in mice
Creators Name:	Tsai, J.J. and Velardi, E. and Shono, Y. and Argyropoulos, K.V. and Holland, A.M. and Smith, O.M. and Yim, N.L. and Rao, U.K. and Kreines, F.M. and Lieberman, S.R. and Young, L.F. and Lazrak, A. and Youssef, S. and Fu, Y.Y. and Liu, C. and Lezcano, C. and Murphy, G.F. and Na, I.K. and Jenq, R.R. and Hanash, A.M. and Dudakov, J.A. and van den Brink, M.R.M.
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.
Keywords:	Acute Disease, Allografts, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Experimental Neoplasms, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Knockout Mice, Lymphocyte Activation, NF-E2-Related Factor 2, Animals, Mice
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	132
Number:	26
Page Range:	2763-2774
Date:	27 December 2018
Official Publication:	https://doi.org/10.1182/blood-2017-10-812941
PubMed:	View item in PubMed

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