The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15

Rebecca B. Delconte, Wei Shi, Priyanka Sathe, Takashi Ushiki, Cyril Seillet, Martina Minnich, Tatiana B Kolesnik, Lucille C. Rankin, Lisa A Mielke, Jian-Guo Zhang, Meinrad Busslinger, Mark J. Smyth, Dana S. Hutchinson, Stephen L Nutt, Sandra E Nicholson, Warren S. Alexander, Lynn M. Corcoran, Eric Vivier, Gabrielle T Belz, Sebastian CarottaNicholas D Huntington

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94 Citations (Scopus)


The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only 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. Id2 is essential for natural killer cell development. Huntington and colleagues demonstrate that Id2 acts as a rheostat to control IL-15 receptor signaling and natural killer cell fate.

Original languageEnglish
Pages (from-to)103-115
Number of pages13
Issue number1
Publication statusPublished - 19 Jan 2016

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