PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness.
Bottom Line: It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation.Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development.Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1-mTOR-E4BP4-CD122 signaling.
Affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.Show MeSH
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Mentions: E4BP4 was reported to be the most specific transcription factor required for the NK cell lineage development (Gascoyne et al., 2009; Kamizono et al., 2009), but how it is regulated remains unknown. A real-time PCR assay revealed that IL-15 could preferentially and significantly up-regulate mRNAs encoding E4BP4 and Eomes (Fig. 1 A). To evaluate the E4BP4 protein level, we developed an intracellular staining assay to quantify its dynamic changes before and after IL-15 stimulation. To our surprise, E4BP4 was rarely detectable in resting NK cells. Upon IL-15 triggering, E4BP4 exhibited a more than fivefold increase in NK cells, and Eomes, which is considered to be involved downstream of E4BP4 (Male et al., 2014), exhibited slight up-regulation (Fig. 1 B). However, T-bet expression was not enhanced by IL-15 stimulation (Fig. 1 B).
Affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.