Impaired function of Vγ9Vδ2 T cells in frail elderly

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. 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. 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.