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Enhanced cytotoxicity of aging associated NKG2C + CD8 + T cells in ankylosing spondylitis via HLA-B27

  • 1State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Science, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai, China.
  • 2State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
  • 3Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China.
  • 4Department of Anthropology and Human Genetics, Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
  • 5State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China. jcwang@fudan.edu.cn.
  • 6Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China. jcwang@fudan.edu.cn.
  • 7Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital, Shanghai, China. zhuqigh540@126.com.
  • 8Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China. zhuqigh540@126.com.
  • 9State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Science, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai, China. liu_jing@fudan.edu.cn.
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June 14, 2025

Abstract

BACKGROUND

This study aims to explore the common mechanisms between aging and the pathogenesis of ankylosing spondylitis (AS) and to identify potential therapeutic targets.

METHODS

A total of 87 patients with AS and matched controls were analyzed via multidimensional flow cytometry to examine the peripheral blood immune signature. Single-cell RNA sequencing was employed to characterize T-cell subsets. The infiltration of Ly49h + cells (the murine homolog of NKG2C) was observed in a collagen-induced arthritis mouse model, and functional experiments were conducted to validate the cytotoxicity of NKG2C + CD8 + T cells. The mechanisms were further confirmed via the use of HLA-B27 transgenic mice and RNA-sequencing.

RESULTS

The peripheral blood immune signature of AS patients exhibited dysregulation similar to that observed during aging. NKG2C + CD8 + T cells activated the PI3K‒Akt signaling pathway and increased phagocytosis in AS patients. HLA-B27 stimulation significantly increased the cytotoxicity of this subset, an effect that could be reversed by NKG2C blockade. In HLA-B27 transgenic mice, Ly49h + T cells exhibited significantly enhanced degranulation ability. RNA sequencing validated the activation of the PI3K‒Akt pathway in NKG2C + CD8 + T cells by HLA-B27.

CONCLUSIONS

HLA-B27 drives the cytotoxicity of aging-related NKG2C + CD8 + T cells via activation of the PI3K‒Akt signaling pathway. Targeting NKG2C inhibition may represent a novel therapeutic strategy for AS. This study elucidates the association between immune aging and the pathogenesis of AS, providing theoretical evidence for clinical intervention.

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