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

Jennifer J Tsai, Enrico Velardi, Yusuke Shono, Kimon V Argyropoulos, Amanda M Holland, Odette M Smith, Nury L Yim, Uttam K Rao, Fabiana M Kreines, Sophie R Lieberman, Lauren F Young, Amina Lazrak, Salma Youssef, Ya-Yuan Fu, Chen Liu, Cecilia Lezcano, George F Murphy, Il-Kang Na, Robert R Jenq, Alan M HanashJarrod A Dudakov, Marcel R M van den Brink

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2763-2774
Number of pages12
JournalBlood
Volume132
Issue number26
DOIs
Publication statusPublished - Dec 27 2018
Externally publishedYes

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    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., ... van den Brink, M. R. M. (2018). Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice. Blood, 132(26), 2763-2774. https://doi.org/10.1182/blood-2017-10-812941