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

O'Sullivan and colleagues identify that the transcription factor Fli1 plays important roles in controlling the establishment of NK cell memory. 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 (NKeff) 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(+) NKeff 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.

Automated summary

The transcription factor Fli1 plays a critical role in controlling the formation of memory cells in natural killer (NK) cells. Single-cell RNA sequencing revealed the presence of two distinct effector NK cell populations. Memory precursor NK cells showed enhanced survival and differentiated into memory NK cells. MP NK cells exhibited different transcriptional and epigenetic signatures compared to other cells.