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Background <p>Frailty, a geriatric syndrome of multisystem physiological decline, elevates vulnerability to adverse health outcomes and involves immunosenescence. While T cell dysfunction is implicated, alterations in the major circulating γδ T cell subset, Vγ9Vδ2 T cells, remain largely unexplored in frailty. This study aims to systematically investigate the transcriptomic, phenotypic, and functional alterations of Vγ9Vδ2 T cells in frail older adults to elucidate their potential role in frailty-associated immune dysregulation.</p> Results <p>We isolated Vγ9Vδ2 T cells from 12 frail and 12 non-frail older adults aged 60–100 years, performing Smart RNA-Seq2 transcriptomic profiling on subsets of 7 participants per group. Protein expression measured by flow cytometry and function assessed by cytokine assays were subsequently validated in distinct subsets of 5 participants per group. Transcriptomic analysis revealed over 700 DEGs between groups, enriched in immune pathways. Validation showed Vγ9Vδ2 T cells from frail individuals had reduced activation potential, with CD69 expression approximately one-third lower, and markers of exhaustion, including PD-1 and LAG-3 expression approximately two-fold higher. Functionally, these cells exhibited severely impaired cytotoxicity, shown by reduced IFN-γ, FasL, Granzymes A/B, and Perforin production.</p> Conclusion <p>To our knowledge, our study is among the first to report a distinct exhaustion-like phenotype in Vγ9Vδ2 T cells from frail older adults, characterized by reduced activation, high PD-1, and impaired cyto-toxicity. These findings suggest that Vγ9Vδ2 T-cell dysfunction may represent a component of immune dysregulation in frailty, suggesting a potential link to the increased immune vulnerability observed in these individuals. Targeting Vγ9Vδ2 T cell function thus represents a novel potential therapeutic strategy to mitigate frailty-associated immune deficits and improve health in older adults.</p>

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Impaired function of Vγ9Vδ2 T cells in frail elderly

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Hui Li,
  • Xiaxuan Li,
  • Hangyu Chen,
  • Zhanqun Yang,
  • Mengzhu Zheng,
  • Yuan Xue,
  • Yingying Yan,
  • Jian Lin,
  • Xuan Lai,
  • Long Chen

摘要

Background

Frailty, a geriatric syndrome of multisystem physiological decline, elevates vulnerability to adverse health outcomes and involves immunosenescence. While T cell dysfunction is implicated, alterations in the major circulating γδ T cell subset, Vγ9Vδ2 T cells, remain largely unexplored in frailty. This study aims to systematically investigate the transcriptomic, phenotypic, and functional alterations of Vγ9Vδ2 T cells in frail older adults to elucidate their potential role in frailty-associated immune dysregulation.

Results

We isolated Vγ9Vδ2 T cells from 12 frail and 12 non-frail older adults aged 60–100 years, performing Smart RNA-Seq2 transcriptomic profiling on subsets of 7 participants per group. Protein expression measured by flow cytometry and function assessed by cytokine assays were subsequently validated in distinct subsets of 5 participants per group. Transcriptomic analysis revealed over 700 DEGs between groups, enriched in immune pathways. Validation showed Vγ9Vδ2 T cells from frail individuals had reduced activation potential, with CD69 expression approximately one-third lower, and markers of exhaustion, including PD-1 and LAG-3 expression approximately two-fold higher. Functionally, these cells exhibited severely impaired cytotoxicity, shown by reduced IFN-γ, FasL, Granzymes A/B, and Perforin production.

Conclusion

To our knowledge, our study is among the first to report a distinct exhaustion-like phenotype in Vγ9Vδ2 T cells from frail older adults, characterized by reduced activation, high PD-1, and impaired cyto-toxicity. These findings suggest that Vγ9Vδ2 T-cell dysfunction may represent a component of immune dysregulation in frailty, suggesting a potential link to the increased immune vulnerability observed in these individuals. Targeting Vγ9Vδ2 T cell function thus represents a novel potential therapeutic strategy to mitigate frailty-associated immune deficits and improve health in older adults.