Chen Xu, Zhang Yue, Chen Yan, Qin Wei, Cheng Tingting, Wang Shiyu, Xu Yajing
Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Changsha, Hunan, China.
Transplantation. 2025 Jul 1;109(7):1152-1165. doi: 10.1097/TP.0000000000005289. Epub 2025 Feb 7.
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.
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.
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.
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.
目前的研究表明，核因子（红系衍生2）样2（NRF2）在T细胞中兼具促炎和抗炎能力，但其在急性移植物抗宿主病（aGVHD）CD4 + T细胞中的具体功能仍未得到探索。
本研究旨在测定有或无aGVHD患者CD4 + T细胞内的NRF2水平，并分析T细胞受体激活与NRF2表达之间的相关性。使用RNA测序检测NRF2过表达后CD4 + T细胞表达谱的变化，并对测序结果进行功能富集分析。最后，用NRF2抑制剂处理aGVHD CD4 + T细胞后，检测相关通路分子的表达。
我们的研究结果表明，与非aGVHD组患者相比，aGVHD组患者CD4 + T细胞中NRF2表达显著上调，且其表达水平与aGVHD的严重程度相关。此外，CD4 + T细胞中的T细胞受体激活可提高NRF2表达。NRF2抑制的CD4 + T细胞激活后，T细胞激活标志物的表达水平明显低于未抑制NRF2的CD4 + T细胞。测序分析确定了NRF2过表达后发生变化的904个基因。这些基因被分为288个基因子集，包括T细胞受体信号转导、Janus激酶1/信号转导和转录激活因子1（JAK1-STAT1）信号传导、辅助性T细胞17（Th17）细胞分化等通路。最终，用NRF2抑制剂处理aGVHD患者的CD4 + T细胞导致JAK1-STAT1信号传导和Th17细胞显著下调。
aGVHD患者CD4 + T细胞中NRF2表达升高，通过增强T细胞激活、放大JAK1/STAT1信号传导和引发Th17/调节性T细胞比例失衡，启动并加剧aGVHD。
