Deng Jun, Zhu Junling, Jiang Xiaoyue, Yao Chao, Chen Haifeng, Ding Yanjie, Niu Peng, Chen Qian, Ding Huihua, Shen Nan
Shanghai Institute of Rheumatology, Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Theranostics. 2025 Mar 31;15(11):5029-5044. doi: 10.7150/thno.107418. eCollection 2025.
Programmed cell death protein 1 (PD-1)-expressing CD8 T cells are typically associated with exhaustion in cancer and infections, but their role in autoimmune diseases, particularly lupus nephritis (LN), remains less understood. Understanding the characteristics and functions of PD-1CD8 T cells in LN could help identify novel therapeutic strategies. We analyzed the abundance and phenotypes of PD-1CD8 T cells in LN patients and NZB/W F1 mice. Single-cell RNA sequencing (scRNA-seq) was used to delineate subsets and TCR clonal diversity in PD-1CD8 T cells in NZB/W F1 mice. The therapeutic efficacy of a PD-L1 Fc fusion protein on kidney pathology and proteinuria in NZB/W F1 mice was evaluated. In addition, the inhibitory mechanism of PD-1 in CD8 T cells were further explored using RNA-seq, q-PCR, flow cytometry, and Western blot. PD-1CD8 T cells were enriched in LN patients and NZB/W F1 mice, exhibiting elevated activation markers and cytotoxic molecules compared to PD-1 cells. scRNA-seq identified seven distinct subsets with diverse effector functions and robust TCR clonal expansion in the kidney of NZB/W F1 mice with severe disease. PD-L1 Fc treatment reduced kidney damage and proteinuria in NZB/W F1 mice, which correlated with decreased frequencies of PD-1CD8 and IFN-γCD8 T cells. Mechanistically, PD-L1 Fc inhibited Stat1 phosphorylation, T-bet expression, and IFN-γ production in CD8 T cells. These findings show that PD-1CD8 T cells in LN are hyperactive, clonally expanded, and contribute to disease progression. Targeting the PD-1/PD-L1 pathway with PD-L1 Fc effectively reduced kidney pathology in a murine model of LN, underscoring the potential of modulating PD-1 signaling as a treatment strategy for LN.
表达程序性细胞死亡蛋白1（PD-1）的CD8 T细胞通常与癌症和感染中的耗竭相关，但其在自身免疫性疾病，特别是狼疮性肾炎（LN）中的作用仍了解较少。了解LN中PD-1⁺ CD8 T细胞的特征和功能有助于确定新的治疗策略。我们分析了LN患者和NZB/W F1小鼠中PD-1⁺ CD8 T细胞的丰度和表型。采用单细胞RNA测序（scRNA-seq）来描绘NZB/W F1小鼠中PD-1⁺ CD8 T细胞的亚群和TCR克隆多样性。评估了PD-L1 Fc融合蛋白对NZB/W F1小鼠肾脏病理和蛋白尿的治疗效果。此外，使用RNA测序、q-PCR、流式细胞术和蛋白质免疫印迹进一步探索了PD-1在CD8 T细胞中的抑制机制。与PD-1⁻细胞相比，PD-1⁺ CD8 T细胞在LN患者和NZB/W F1小鼠中富集，表现出活化标志物和细胞毒性分子升高。scRNA-seq在患有严重疾病的NZB/W F1小鼠肾脏中鉴定出七个具有不同效应功能和强大TCR克隆扩增的不同亚群。PD-L1 Fc治疗减少了NZB/W F1小鼠的肾脏损伤和蛋白尿，这与PD-1⁺ CD8和IFN-γ⁺ CD8 T细胞频率降低相关。机制上，PD-L1 Fc抑制CD8 T细胞中的Stat1磷酸化、T-bet表达和IFN-γ产生。这些发现表明，LN中的PD-1⁺ CD8 T细胞过度活跃、克隆扩增并促进疾病进展。用PD-L1 Fc靶向PD-1/PD-L1途径可有效减轻LN小鼠模型中的肾脏病理，强调调节PD-1信号作为LN治疗策略的潜力。
