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.