Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

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.

Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS

“…Furthermore, there was a trend towards upregulation of IL-15 concentrations. IL-15 has been associated with proliferation and activation of NK cells that were increased in the CSF of DMFtreated patients, although this finding was not significant (Wang and Zhao, 2021). Meningeal inflammation and slowly expanding lesions compose key elements in the pathogenesis of progressive MS (Elliott et al, 2019;Magliozzi et al, 2018).…”

Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

“…We have defined two pathways whereby Zhx2 controls NK cell maturation and function. One is that Zhx2 down-regulates NK cell responses to IL-15, the cytokine crucial for NK cell development and survival ( Wang et al, 2019 ; Wang and Zhao, 2021 ). Deletion of Zhx2 in NK cells resulted in increased activity of AKT and STAT5, two major signaling pathways of IL-15.…”

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

“…One of the reasons is most likely a remotely orchestrated IL-15R downregulation in cancer-altered BM stroma ( 170 ). The IL-15/IL-15R axis is indeed an important NK cell development regulator and proliferation inducer, acting via IL-2Rβ (CD122), and JAK/STAT, Ras/MEK/MAPK, or PI3K/AKT pathways ( 171 , 172 ). Mutations in GATA2 (absent CD56bright cells), MCM4 (absent CD56dim cells), IL2-R, JAK3, STAT5 , and IL-15R were associated with impaired NK maturation ( 44 , 173 , 174 ).…”