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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice

“…showed that Nrf2 inhibits effector T cell activities independently of Tregs and that Nrf2‐mediated inflammatory effects in the context of autoimmunity required the integrity of Nrf2 mediated functional modulations of multiple cell lineages . More recently, it was reported that absence of Nrf2 in donor T cells enhanced persistence of Tregs and reduced systemic inflammation in a graft‐versus‐host disease in mice . Our study is the first to analyze Nrf2 activation specifically in Tregs by using Foxp3 cre Keap fl/fl mice and Foxp3 cre Keap fl/fl cell reconstituted BM chimeras.…”

“…TCR stimulation induces nuclear Nrf2 translocation and protein expression [10]. To further address the relevance of Nrf2 activity for T cell differentiation, we analyzed Nrf2 activation in isolated T cells during subsequent differentiation into distinct T cell subsets.…”

Keap1-Nrf2 System Plays an Important Role in Invariant Natural Killer T Cell Development and Homeostasis

“…Activation of Nrf2 has been shown to negatively affect the maturation and effector functions in the related natural killer (NK) cells (Boss et al, 2018). Keap1 has been linked to T cell functions and thereby to inflammation (Ahmed et al, 2017; Noel et al, 2018; Tsai et al, 2018). T cell-specific deletion of Keap1 did not affect the conventional T cell numbers or percentages in the thymus, indicating that Keap1-Nrf2 is dispensable for T cell development (Noel et al, 2015).…”

The role of Nrf2 in acute and chronic muscle injury

“…In our studies, contrary to the expectations, in ammation was not exacerbated in dystrophic muscles lacking transcriptionally active Nrf2 both when total in ammatory extent was evaluated on histological sections and by detailed analysis of immune subtypes by ow cytometry. Of note, despite the fact T h and T c lymphocytes contribute to the pathogenesis of DMD (6) and their functions may be regulated by Nrf2 (44), their numbers were changed neither by dystrophin nor Nrf2 de ciency. An interesting nding of our study is related to the NK cells' abundance -their number was signi cantly decreased in Nrf2 tKO mdx mice in comparison to mdx, in which they are elevated in the muscles (45).…”