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Background <p>This study aims to explore the common mechanisms between aging and the pathogenesis of ankylosing spondylitis (AS) and to identify potential therapeutic targets.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月14日

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  • Kunhai Tang,
  • Xiaobei Ma,
  • Jian Gao,
  • Lilu Zu,
  • Yanyun Ma,
  • Dachun Zhuo,
  • Chenyuan Wu,
  • Yulong Tang,
  • Feng Qian,
  • Li Jin,
  • Jiucun Wang,
  • Qi Zhu,
  • Jing Liu

摘要

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.