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

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Item Type:	Article
Title:	Nrf2 regulates CD4(+) T cell-induced acute graft-versus-host disease in mice
Creators Name:	Tsai, J.J., Velardi, E., Shono, Y., Argyropoulos, K.V., Holland, A.M., Smith, O.M., Yim, N.L., Rao, U.K., Kreines, F.M., Lieberman, S.R., Young, L.F., Lazrak, A., Youssef, S., Fu, Y.Y., Liu, C., Lezcano, C., Murphy, G.F., Na, I.K., Jenq, R.R., Hanash, A.M., 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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