AUTHOR=Ni Xiang , Fu Binqing , Zhang Jinghe , Sun Rui , Tian Zhigang , Wei Haiming TITLE=Cytokine-Based Generation of CD49a+Eomes−/+ Natural Killer Cell Subsets JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02126 DOI=10.3389/fimmu.2018.02126 ISSN=1664-3224 ABSTRACT=

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 in vitro 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.