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

CD8 ⁺ virtual memory T (T _VM ) cells are memory-like cells that 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 transcription factor Aiolos as a negative regulator of T _VM cells. We observed higher quantities of T _VM cells in the spleens of uninfected Aiolos-deficient ( Ikzf3 ^-/- ) mice relative to wild-type (WT). Furthermore, Ikzf3 ^-/- T _VM cells produced higher levels of IFN-γ and granzyme B. In addition, we found that Ikzf3 ^-/- T _VM cells accumulated to higher quantities in the lungs within 24 hours of influenza virus infection. In line with enhanced T _VM functional capacity and lung trafficking, Aiolos-deficient mice cleared virus more rapidly and exhibited reduced morbidity relative to WT animals. Mechanistically, we observed that Aiolos represses the T _VM transcriptional regulator Eomes and the IL-15R subunit CD122 (IL-15Rβ/IL-2Rβ), known contributors of T _VM cell generation. Collectively, these findings establish Aiolos as a novel molecular repressor of T _VM generation and function.