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

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

Edité par CCSD ; Elsevier -

International audience. 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.

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