The transcription factor Fli1 restricts the formation of memory precursor NK cells during viral infection

Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as memory formation. However, the molecular mechanisms by which NK cells persist to form memory cells are not well understood. Using single-cell RNA sequencing, we identified two distinct effector NK cell (NK_eff) populations following mouse cytomegalovirus infection. Ly6C^- memory precursor (MP) NK cells showed enhanced survival during the contraction phase in a Bcl2-dependent manner, and differentiated into Ly6C⁺ memory NK cells. MP NK cells exhibited distinct transcriptional and epigenetic signatures compared with Ly6C⁺ NK_eff cells, with a core epigenetic signature shared with MP CD8⁺ T cells enriched in ETS1 and Fli1 DNA-binding motifs. Fli1 was induced by STAT5 signaling ex vivo, and increased levels of the pro-apoptotic factor Bim in early effector NK cells following viral infection. These results suggest that a NK cell-intrinsic checkpoint controlled by the transcription factor Fli1 limits MP NK formation by regulating early effector NK cell fitness during viral infection.