Glomerular endothelial cells eliminate nicotinamide adenine dinucleotide to instruct CD103+T cells in human lupus nephritis

• 成果类型: Article
• 署名作者: Jia, Li; Liu, Mengdi; Ji, Huiyan; Lei, Jiaxin; Su, Danhua; Li, Lingyi; Liu, Ting; Yuan, Fenghong; Xu, Lin; Cao, Qinghua; Zhang, Huimin; Wen, Zhenke
• 署名单位: Soochow University - China; Soochow University - China; Nanjing Medical University; Jiangnan University; Zunyi Medical University; University of Sydney; Kolling Institute of Medical Research; Royal North Shore Hospital; University of California System; University of California Riverside
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2507422122
• 发表日期: 2025-12-16
• 页码: e2507422122
• 关键词: Lupus nephritis; CD103+T cell; endothelial cell; MEMORY T-CELLS; DARATUMUMAB; protects; MODEL; CD38

摘要

Lupus nephritis (LN), which is characterized by the accumulation of DNA- containing immune complexes (ICs), is the leading cause of death in patients with systemic lupus erythematosus (SLE). While growing evidence highlights the central role of CD103+ T cells in shaping the immune landscape of regional tissues, mechanisms driving the cell differentiation in LN remain largely unexplored. In this study, we identified an increased frequency of CD4+CD103+ T cells within the kidneys of SLE patients. Importantly, glomerular endothelial cells (ECs) from human LN tissues were found to promote the differentiation of CD4+CD103+ T cells by upregulating B lymphocyte-induced resulted in a reduced frequency of renal CD4+CD103+ T cells and alleviated LN in humanized SLE chimeras. Mechanistically, LN- associated ECs, triggered by circulating DNA from SLE patients, exhibited elevated CD38 expression via the cGAS- STING signaling pathway. This facilitated the transfer of CD38 into CD4+ T cells through an exosome- dependent mechanism, leading to the depletion of nicotinamide adenine dinucleotide (NAD+) levels in CD4+ T cells. The resulting NAD+ depletion impaired the PARP1- mediated ADP- ribosylation of early growth response protein 1 (EGR1), which, in turn, enhanced Blimp- 1 transcription and promoted CD103+ T cell differentiation. Targeting the cGAS/STING- CD38- EGR1 axis effectively reduced renal CD103+ T cell accumulation and inhibited LN progression in humanized SLE chimeras. Thus, ECs facilitate NAD+ depletion to drive CD103+ T cell differentiation, presenting a cellular mechanism underlying LN pathogenesis and a potential therapeutic target for the clinical management of human LN.