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

CD8+ virtual memory T (TVM) cells rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM 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 TVM cell programming. We observe enhanced frequencies and numbers of TVM 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-/- TVM 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 TVM cell functionality. Mechanistically, Aiolos represses the expression of the transcription factor Eomes and the IL-15R subunit CD122, known positive regulators of TVM gene program. Collectively, these findings establish Aiolos as a molecular repressor of TVM programming and responses.