2. Academic Validation
  3. Elevated type I IFN signalling directly affects CD8+ T-cell distribution and autoantigen recognition of the skeletal muscles in active JDM patients

Elevated type I IFN signalling directly affects CD8+ T-cell distribution and autoantigen recognition of the skeletal muscles in active JDM patients

  • J Autoimmun. 2024 Apr 30:146:103232. doi: 10.1016/j.jaut.2024.103232.
Baozhen Huang 1,  Huiyu Li 2,  Qian Jiang 3,  Yucong Li 1,  Zhaowei Jiang 1,  Huijuan Cao 2,  Shaoxi Wang 4,  Xinluan Wang 5,  Jianguo Li 6,  Gang Li 7
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 3 Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China; Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Singleron Biotechnologies, Nanjing, China.
  • 5 Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: xl.wang@siat.ac.cn.
  • 6 Department of Rheumatology and Immunology, Children's Hospital Affiliated to Capital Institute of Pediatrics, China. Electronic address: jianguo_li6@hotmail.com.
  • 7 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. Electronic address: gangli@cuhk.edu.hk.
PMID: 38692172 DOI: 10.1016/j.jaut.2024.103232
Abstract

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.

Keywords

CD8(+) T cell; IFN; Juvenile dermatomyositis; MHC I; Muscle.

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