GSE176208
Fli1 drives the terminal differentiation of a memory precursor-like NK cell during viral infection
Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived memory cells following viral infection. However, the molecular mechanisms by which clonally expanded effector NK (NKeff) cells persist to form memory cells is not well understood. Utilizing single cell RNA sequencing, we identify two Ly49H+ NKeff cell populations following mouse cytomegalovirus (MCMV) infection defined by the cell surface protein Ly6C. Ly6C– NKeff cells displayed enhanced survival during the contraction phase in a BCL2-dependent manner. Ly6C– NKeff cells displayed distinct transcriptional and epigenetic signatures compared to Ly6C+ NKeff cells, with a core epigenetic signature shared with memory precursor (MP) CD8+ T cells enriched in ETS1 and Fli1 DNA-binding motifs. Fli1 regulated memory NK cell fate by promoting terminal maturation and decreased persistence of contracting NK cells. Our results suggest that memory NK cells, similar to memory T cells, are generated by a subset of epigenetically distinct MP cell states that preferentially survive during the contraction phase of the response to viral infection. Overall design: bulk RNA-seq, ATAC-seq and scRNA-seq on Ly6C+ and Ly6C- NK cells.