Elderly female CTLs maintain their initial activation and cytotoxicity independent of IL-2

Cytotoxic T lymphocytes (CTLs) are crucial for immune defence, with interleukin-2 (IL-2) playing a central role in their activation, proliferation, and effector functions. However, the impact of IL-2 on CTLs during ageing and across sexes remains poorly understood. In this study, we investigated the age- and sex-specific influence of IL-2 on CTL activation and cytotoxicity. CTLs from adult mice demonstrated a strong dependence on IL-2 for activation and function, while CTLs from elderly female mice exhibited reduced IL-2 dependence and maintained cytotoxicity under suboptimal IL-2 conditions. This reduction in IL-2 reliance was linked to increased autocrine IL-2 production, enhanced expression of activation markers (CD25, CD69), and effector molecules (perforin, granzyme B). Additionally, elderly female CTLs secreted higher levels of pro-inflammatory cytokines, such as TNF-α and IL-17 A, which may enhance immune responses but also contribute to inflammation if dysregulated. In contrast, CTLs from elderly male mice displayed reduced cytotoxicity and cytokine secretion under low IL-2 conditions. These findings reveal significant sex-specific adaptations in CTL function during ageing, highlighting that elderly female mice can maintain immune function with less reliance on IL-2. This underscores the need for immune therapies that account for age- and sex-related differences in IL-2 signalling and cytokine regulation.