Cytokine-Based Generation of CD49a + Eomes -/+ Natural Killer Cell Subsets

Recent studies have identified CD49a Eomes and CD49a Eomes subsets of tissue-resident NK (trNK) cells in different organs of the mouse. However, the characteristics of CD49a Eomes NK cell development and the regulation of Eomes expression in NK cells remain unclear. Here, we established an cytokine-based feeder-free system in which bone marrow progenitor cells differentiate into CD49a NK cells. IL-15 was identified as being the key cytokine in this system that supported the development and maintenance of CD49a NK cells. The CD49a NK cells generated were Eomes CD49b and shared the same phenotype as hepatic trNK cells. IL-4 induced the expression of Eomes in generated NK cells and converted them into CD49a Eomes cells, which were phenotypically and functionally similar to uterine trNK cells. Moreover, the IL-4/STAT6 axis was identified as being important in the generation of CD49a Eomes induced NK cells. Collectively, these studies describe an approach to generate CD49a Eomes subsets of NK cells and demonstrate important roles for IL-15 and IL-4 in the differentiation of these cells. These findings have potential for developmental research underlying the generation of different subsets of NK cells and the application of adoptive NK cell transfer therapies.