Aging Reshapes γ/δ T‐Cell Immunity Through a Type I Interferon–Foxo1 Axis

ABSTRACT Aging is associated with profound alterations in immune cell composition and function, yet the impact on peripheral γ/δ T‐cell subsets remains incompletely understood. Here, we show that the peripheral γ/δ T‐cell compartment is markedly remodeled with age in mice. Specifically, innate‐like Ly‐6C − CD44 hi γ/δ T cells expand in secondary lymphoid organs (SLOs) of aged mice, while adaptive‐like subsets decline. This age‐related shift is accompanied by enhanced functionality, with Ly‐6C − CD44 hi γ/δ T cells from aged SLOs displaying increased IL‐17 production both ex vivo and in vivo following LPS challenge. Mechanistically, this functional remodeling correlates with a significant decrease in the expression of the transcription factor Foxo1 in Ly‐6C − CD44 hi γ/δ T cells. Type I interferon signaling contributes to the age‐dependent downregulation of Foxo1, as Ly‐6C − CD44 hi γ/δ T cells from aged mice lacking the IFN‐α receptor maintain Foxo1 expression and exhibit reduced IL‐17 production. Collectively, our findings reveal that aging, through type I interferon–driven modulation of Foxo1, promotes the expansion and enhanced pro‐inflammatory activity of innate‐like γ/δ T cells. These changes may reinforce immune surveillance in secondary lymphoid organs but could also contribute to age‐associated immune dysregulation and inflammation.