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

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.

Human liver-derived CXCR6+ NK cells are predominantly educated through NKG2A and show reduced cytokine production

“…The important role of IL‐15 in this context was further confirmed by Ni et al. demonstrating that the generation of murine CD49a + NK cells from Bone marrow cells required IL‐15 . Overall, these data support the idea that NK cells may exhibit cytokine‐induced plasticity that is required for tissue‐homing in specific disease settings as well as general homeostasis.…”

Innate and adaptive immune responses following PD‐L1 blockade in treating chronic murine alveolar echinococcosis

“…[36][37][38] NK cells in the liver are very frequent, divided between cNK (CD49b + NK) and resident NK cells (CD49a + NK). [39][40][41][42] In this present study, total NK cells were significantly increased due to E. multilocularis infection, with also an increasing of NKT cells. NK cells are reported to be protective at the early stages of parasitic infections.…”

On the Way to Become a Natural Killer Cell

“…IL-4 has been recently described of being able to induce the development of tissue-resident NK lymphocytes in mice by converting CD49a pos /Eomes neg NK cells into their functional CD49a pos /Eomes pos counterparts (124). Since CD49a pos /Eomes neg NK cell subset is considered a liver-resident NK cell subset in mice, these findings could be relevant for a better understanding of the specific tissue-resident generation of NK cells (125).…”