Tissue-Resident Natural Killer (NK) Cells Are Cell Lineages Distinct From Thymic and Conventional Splenic NK Cells (part 1)

Natural killer (NK) cells belong to the innate immune system where they can control virus infections and developing tumors by cytotoxicity and production of inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells found in the spleen. Recently, we described two populations of NK cells within the liver, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, the lineage relationship of trNK to cNK cells was unclear because trNK cells display a phenotype associated with immature, developing cNK cells. Moreover, liver trNK cells could be related to thymic NK cells or alternatively, a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis of mice deficient in several transcription factors to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells, especially because they do not require NFIL3 (E4BP4), the previously described NK cellspecification factor. Analysis of other tissues indicate the presence of trNK cells in skin and uterus with different transcription factor requirements. Thus, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells.