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 identify a potential role for PDK1-medated signaling in NK cell physiology, we extensively analyzed NK cell development and function in PDK1−/− mice. Compared with PDK1-sufficient mice, PDK1−/− mice exhibited a nearly 95% reduction in the number of NK cells in the spleen and bone marrow (Fig. 2, A and B). The remarkable reduction in NK cell pool could also be found in other lymphoid organs, including the lymph nodes, liver, and lungs (Fig. 2 B). To investigate the cell-intrinsic effect of PDK1 for NK cell development, bone marrow mixtures were adoptively transferred into sublethally irradiated immunodeficient RAG1−/−γc− mice. In contrast to CD45.2+ WT, PDK1−/− bone marrow cells failed to reconstitute NK cell pool efficiently (Fig. 2 C), suggesting the critical requirement for PDK1 in NK cell development is cell intrinsic.
Affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.