The helix-loop-helix protein Id2 governs NK cell fate by tuning their sensitivity to interleukin-15 Academic Article uri icon


  • 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.


  • 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

publication date

  • 2016