{"title":"异常表达核因子（红细胞衍生2）样2通过调节CD4+ T淋巴细胞的激活和分化参与aGVHD","authors":"Xu Chen, Yue Zhang, Yan Chen, Wei Qin, Tingting Cheng, Shiyu Wang, Yajing Xu","doi":"10.1097/TP.0000000000005289","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":23316,"journal":{"name":"Transplantation","volume":" ","pages":"1152-1165"},"PeriodicalIF":5.0000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180704/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Aberrantly Expressed Nuclear Factor (Erythroid-derived 2)-Like 2 Participates in aGVHD by Modulating the Activation and Differentiation of CD4 + T Lymphocytes.\",\"authors\":\"Xu Chen, Yue Zhang, Yan Chen, Wei Qin, Tingting Cheng, Shiyu Wang, Yajing Xu\",\"doi\":\"10.1097/TP.0000000000005289\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":23316,\"journal\":{\"name\":\"Transplantation\",\"volume\":\" \",\"pages\":\"1152-1165\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180704/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Transplantation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/TP.0000000000005289\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/7 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transplantation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/TP.0000000000005289","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
The Aberrantly Expressed Nuclear Factor (Erythroid-derived 2)-Like 2 Participates in aGVHD by Modulating the Activation and Differentiation of CD4 + T Lymphocytes.
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.
期刊介绍：
The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year.
Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.
Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed.
The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
