Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells in mice

CD8⁺ virtual memory T (T_VM) cells rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that T_VM cells arise independently of foreign antigen encounter, the mechanisms governing their development are not fully understood. Here, we identify the Ikaros transcription factor Aiolos as a negative regulator of T_VM cell programming. We observe enhanced frequencies and numbers of T_VM in the spleen, liver, and blood of unchallenged Aiolos-deficient (Ikzf3^-/-) mice and in the lungs 1-day post-infection with influenza A virus (IAV). Furthermore, Ikzf3^-/- T_VM cells produce elevated IFN-γ and granzyme B in response to cytokine stimulation. Importantly, Aiolos-deficient mice control IAV more rapidly and exhibit reduced morbidity, indicating enhanced T_VM cell functionality. Mechanistically, Aiolos represses the expression of the transcription factor Eomes and the IL-15R subunit CD122, known positive regulators of T_VM gene program. Collectively, these findings establish Aiolos as a molecular repressor of T_VM programming and responses.