Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China; Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China; The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
J Autoimmun. 2024 Jun;146:103232. doi: 10.1016/j.jaut.2024.103232. Epub 2024 Apr 30.
The link between type I IFN and adaptive immunity, especially T-cell immunity, in JDM still remained largely unclear. This study aimed to understand the effect of elevated type I IFN signaling on CD8 T cell-associated muscle damage in juvenile dermatomyositis (JDM). This study used flow cytometry (FC) and RT‒PCR were used to examine the circulating cell ratio and type I IFN response. And scRNA-seq was used to examine peripheral immunity in 6 active JDM patients, 3 stable JDM patients, 3 juvenile IMNM patients and 3 age-matched healthy children. In vivo validation experiments were conducted using a mouse model induced by STING agonists and an experimental autoimmune myositis model (EAM). In vitro experiments were conducted using isolated CD8 T-cells from JDM patients and mice. We found that active JDM patients showed an extensive type I IFN response and a decreased CD8 T-cell ratio in the periphery (P < 0.05), which was correlated with muscle involvement (P < 0.05). Both new active JDM patients and all active JDM patients showed decreased CD8 TCM cell ratios compared with age and gender matched stable JDM patients (P < 0.05). Compared with new pediatirc systemic lupus erythematosus (SLE) patients, new active JDM patients displayed decreased CD8 T-cell and CD8 TCM cell ratios (P < 0.05). Active JDM patient skeletal muscle biopsies displayed an elevated type I IFN response, upregulated MHC-I expression and CD8 T-cell infiltration, which was validated in EAM mice. sc-RNAseq demonstrated that type I IFN signalling is the kinetic factor of abnormal differentiation and enhances the cytotoxicity of peripheral CD8 T cells in active JDM patients, which was confirmed by in vivo and in vitro validation experiments. In summary, the elevated type I IFN signalling affected the differentiation and function of CD8 T cells in active JDM patients. Skeletal muscle-infiltrating CD8 T cells might migrate from the periphery under the drive of type I IFN and increased MHC I signals. Therapies targeting autoantigen-specific CD8 T cells may represent a potential new treatment direction.
I 型干扰素与适应性免疫（尤其是 T 细胞免疫）之间的关系在皮肌炎（JDM）中仍然很大程度上不清楚。本研究旨在了解升高的 I 型干扰素信号对 JDM 中 CD8 T 细胞相关肌肉损伤的影响。本研究使用流式细胞术（FC）和 RT-PCR 检查循环细胞比和 I 型 IFN 反应。并使用单细胞 RNA 测序（scRNA-seq）检查 6 名活动期 JDM 患者、3 名稳定期 JDM 患者、3 名青少年免疫介导坏死性肌病（IMNM）患者和 3 名年龄匹配的健康儿童的外周免疫。在体内验证实验中，使用 STING 激动剂诱导的小鼠模型和实验性自身免疫性肌炎模型（EAM）进行。在体外实验中，使用 JDM 患者和小鼠分离的 CD8 T 细胞进行。我们发现，活动期 JDM 患者表现出广泛的 I 型 IFN 反应和外周血 CD8 T 细胞比例降低（P<0.05），这与肌肉受累有关（P<0.05）。与年龄和性别匹配的稳定期 JDM 患者相比，新活动期 JDM 患者和所有活动期 JDM 患者的 CD8 TCM 细胞比例均降低（P<0.05）。与新的儿科系统性红斑狼疮（SLE）患者相比，新活动期 JDM 患者的 CD8 T 细胞和 CD8 TCM 细胞比例降低（P<0.05）。活动期 JDM 患者的骨骼肌活检显示 I 型 IFN 反应升高，MHC-I 表达上调和 CD8 T 细胞浸润，这在 EAM 小鼠中得到验证。sc-RNAseq 表明，I 型 IFN 信号是异常分化的动力学因素，并增强活动期 JDM 患者外周血 CD8 T 细胞的细胞毒性，这通过体内和体外验证实验得到证实。总之，升高的 I 型 IFN 信号影响活动期 JDM 患者 CD8 T 细胞的分化和功能。浸润骨骼肌的 CD8 T 细胞可能在 I 型 IFN 和 MHC I 信号的驱动下从外周迁移而来。针对自身抗原特异性 CD8 T 细胞的治疗可能代表一种潜在的新治疗方向。
