The helix-loop-helix protein ID2 governs NK cell fate by tuning their sensitivity to interleukin-15

The inhibitor of DNA binding 2 (Id2) is essential for NK cell development with its canonical role in this pathway being to antagonize E-proteins, silencing E-box gene expression and subsequent commitment to the T and B cell lineages. However, how E-box genes prevent NK cell development and homeostasis remains enigmatic. Here we identify a key role for Id2 in regulating the threshold for IL-15 receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Deletion of Id2 in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling. Id2-null NK cells displayed impaired IL-15 mediated JAK1/STAT5 phosphorylation, compromised metabolic function and enhanced apoptosis. Remarkably, Id2-null NK cell homeostasis could be fully rescued in vivo by IL-15 receptor stimulation and partially rescued by genetic ablation of Socs3. During normal NK cell maturation we observed an inverse correlation between the expression levels of E-protein target genes and Id2. These results shift the current paradigm on the role of Id2, indicating that it is not only required to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15. Overall design: Transcriptional profiling of wild type and Id2-null natural killer (NK) cells using RNA sequencing

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Delconte RB, Shi W, Sathe P, Ushiki T, Seillet C, Minnich M, Kolesnik TB, Rankin LC, Mielke LA, Zhang JG, Busslinger M, Smyth MJ, Hutchinson DS, Nutt SL, Nicholson SE, Alexander WS, Corcoran LM, Vivier E, Belz GT, Carotta S, Huntington ND