Abstract
Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.
Highlights
Natural killer (NK) cells constitute the third most abundant lineage of lymphocytes in the peripheral blood after B and T cells, accounting for approximately 8–15% of circulating cells in humans or 2–6% in mice [1]
We provide an overview of the specific IL-15 signaling that transcriptionally regulates NK cell development and maturation
Previous studies have uncovered the distinct function of dendritic cell (DC) and macrophages in NK cell development, the exact biological role of IL-15 expression in other hematopoietic cells and diverse stromal cells that reside in the bone marrow (BM) or peripheral blood and organs during NK cell development remains poorly described
Summary
NK cells constitute the third most abundant lineage of lymphocytes in the peripheral blood after B and T cells, accounting for approximately 8–15% of circulating cells in humans or 2–6% in mice [1]. The deletion of Eomes in mice results in significantly decreased CD122 expression at different stages of NK cell maturation [33, 35, 37]. Previous studies have uncovered the distinct function of DCs and macrophages in NK cell development, the exact biological role of IL-15 expression in other hematopoietic cells (myeloid cells and early HSCs) and diverse stromal cells that reside in the BM or peripheral blood and organs during NK cell development remains poorly described.
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