Eomes expression identifies the early bone marrow precursor to classical NK cells.

Natural killer (NK) cells traffic through the blood and mount cytolytic and interferon-γ (IFNγ)-focused responses to intracellular pathogens and tumors. Type 1 innate lymphoid cells (ILC1s) also produce type 1 cytokines but reside in tissues and are not cytotoxic. Whether these differences reflect discrete lineages or distinct states of a common cell type is not understood. Using single-cell RNA sequencing and flow cytometry, we focused on populations of TCF7(+) cells that contained precursors for NK cells and ILC1s and identified a subset of bone marrow lineage-negative NK receptor-negative cells that expressed the transcription factor Eomes, termed Eomes(hi)NK(neg) cells. Transfer of Eomes(hi)NK(neg) cells into Rag2(-/-)Il2rg(-/-) recipients generated functional NK cells capable of preventing metastatic disease. By contrast, transfer of PLZF(+) ILC precursors generated a mixture of ILC1s, ILC2s and ILC3s that lacked cytotoxic potential. These findings identified Eomes(hi)NK(neg) cells as the bone marrow precursor to classical NK cells and demonstrated that the NK and ILC1 lineages diverged early during development.