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

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.