Impaired function of Vγ9Vδ2 T cells in frail elderly

  • Immun Ageing. 2026 Jan 16;23(1):7. doi: 10.1186/s12979-026-00558-8.
Hui Li  #  1  2 ,  Xiaxuan Li  #  3 ,  Hangyu Chen  #  1 ,  Zhanqun Yang  1  2 ,  Mengzhu Zheng  4 ,  Yuan Xue  1  2 ,  Yingying Yan  5 ,  Jian Lin  6  7  8 ,  Xuan Lai  9 ,  Long Chen  10  11
Affiliations
  • 1. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China.
  • 2. Cancer Center, Peking University Third Hospital, Beijing, 100191, China.
  • 3. School of Information and Communication Engineering, Hainan University, Haikou, 570228, China.
  • 4. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 5. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • 6. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • 7. Cancer Center, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • 8. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. [email protected].
  • 9. Department of Geriatrics, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • 10. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • 11. Cancer Center, Peking University Third Hospital, Beijing, 100191, China. [email protected].
  • # Contributed equally.
PMID: 41546035 DOI: 10.1186/s12979-026-00558-8
Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12979-026-00558-8.

Keywords
Aging; Frail; Immunobiology; Vγ9Vδ2 t cell.
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