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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. Hanash, Jarrod A. Dudakov and Marcel R.M. van den Brink

Key points

  • Donor T cells lacking Nrf2 demonstrate ameliorated GVHD.

  • Absence of Nrf2 on donor cells enhanced the persistence of Helios+ nTregs in allograft recipients.

Abstract

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor well known for its role in regulating the cellular redox pathway. While there is mounting evidence suggesting a critical role of 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 of 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 not only characterized a previously unrecognized role of Nrf2 in T-cell function, but also revealed a novel therapeutic target to improve the outcomes of allo-HCT.

  • Submitted October 25, 2017.
  • Accepted October 1, 2018.