Eomes Expression Identifies the Early Bone Marrow Precursor to Classical NK Cells

Classical NK cells are the prototypical type 1 innate lymphocytes mounting cytolytic and IFNγ responses to intracellular pathogens and tumors. A similar but distinct population termed ILC1 was recently described, differing from NK cells in multiple relatively subtle ways, including tissue residency versus recirculation, and expression levels of NK receptors. Whether the differences reflect distinct lineages or mere variations in program expression is not fully understood. Here, using single-cell RNA-sequencing analysis, transcription factor reporter mice, and cell transfers of bone marrow precursors, we identified distinctive, lineage-negative, Eomes-positive, NK receptor-negative cells that, upon transfer in vivo, acquired properties typically associated with classical NK cells, including the capacity to prevent metastatic disease. In contrast, as previously reported, PLZF-high cells predominantly generated ILC1, ILC2, or ILC3. These findings identify the Eomes-expressing NK precursor as the long-elusive bone marrow precursor to classical NK cells and demonstrate that the NK and ILC1 lineages diverge early during development.