The Aberrantly Expressed Nuclear Factor (Erythroid-derived 2)-Like 2 Participates in aGVHD by Modulating the Activation and Differentiation of CD4+ T Lymphocytes

  • Transplantation. 2025 Feb 7. doi: 10.1097/TP.0000000000005289.
Xu Chen  1  2  3 ,  Yue Zhang  1  2  3 ,  Yan Chen  1  2  3 ,  Wei Qin  1  2  3 ,  Tingting Cheng  1  2  3 ,  Shiyu Wang  1  2  3 ,  Yajing Xu  1  2  3
Affiliations
  • 1. Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Changsha, Hunan, China.
  • 3. Hunan Hematology Oncology Clinical Medical Research Center, Xiangya Hospital, Changsha, Hunan, China.
PMID: 39915920 DOI: 10.1097/TP.0000000000005289
Abstract

Background: Current investigation indicates that nuclear factor (erythroid-derived 2)-like 2 (NRF2) possesses both proinflammatory and anti-inflammatory capabilities in T cells, yet its exact function in acute graft-versus-host disease (aGVHD) CD4+ T cells remains unexplored.

Methods: This study aims to determine NRF2 levels within CD4+ T cells of patients with or without aGVHD and analyze the correlation between T-cell receptor activation and NRF2 expression. RNA Sequencing was used to detect changes in the expression profile of CD4+ T cells after overexpression of NRF2, and functional enrichment analysis was performed on the Sequencing results. Finally, after treating aGVHD CD4+ T cells with NRF2 inhibitor, the expression of related pathway molecules was detected.

Results: Our findings demonstrated a significant upregulation of NRF2 expression in CD4+ T cells from patients in the aGVHD group compared with patients in the non-aGVHD group, and its expression level is correlated with the severity of aGVHD. Additionally, T-cell receptor activation in CD4+ T cells elevates NRF2 expression. Postactivation of NRF2-inhibited CD4+ T cells, the expression levels of T-cell activation markers were notably lower than those in non-NRF2-inhibited CD4+ T cells. Sequencing analysis identified 904 genes that changed after NRF2 overexpression. These genes were categorized into 288 gene subsets, encompassing pathways such as T-cell receptor signaling transduction, Janus kinase 1/signal transducer and activator of transcription 1 (JAK1-STAT1) signaling, T helper cell 17 (Th17) cell differentiation, etc. Ultimately, treating CD4+ T cells of aGVHD patients with an NRF2 inhibitor led to a significant downregulation of JAK1-STAT1 signaling and Th17 cells.

Conclusions: Elevated NRF2 expression in CD4+ T cells of patients with aGVHD initiates and exacerbates aGVHD by potentiating T-cell activation, amplifying JAK1/STAT1 signaling, and instigating Th17/regulatory T-cell ratio imbalance.

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