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: To investigate whether the compromised NK cell development and low expression level of CD122 correlated with less E4BP4 induction by IL-15 in PDK1−/− mice, actively dividing PDK1−/− bone marrow cells with enriched HSCs were infected by retroviruses encoding E4BP4 or Eomes. 6 wk after in vivo differentiation, exogenous expression of E4BP4 gave rise to an increase in the NK cell population in PDK1-intact bone marrow group, as reported elsewhere (Fig. 4, A and B; Gascoyne et al., 2009). Importantly, ectopic expression of E4BP4 in PDK1−/− bone marrow cells could recover the CD122+NK1.1+ NK cell population to a great extent (Fig. 4 A, B). Likewise, exogenous E4BP4 expression heightened the expression level of CD122 on PDK1−/− NK cells and prevented the accumulation of the arrested NK1.1int CD122− NK cells in the PDK1−/− bone marrow. Similar results were also obtained when Eomes was ectopically expressed (Fig. 4, A and B). Therefore, the impaired NK cell development in PDK1-deficient mice is largely caused by the defect in E4BP4 induction by IL-15.
Affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.