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 (1) , Gabrielle T. Belz , Sebastian Carotta , Nicholas D. Huntington

1 CIML - Centre d'Immunologie de Marseille - Luminy

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.

Domaines: Immunologie

Rebecca B. Delconte, Wei Shi, Priyanka Sathe, Takashi Ushiki, Cyril Seillet, et al.. The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15. Immunity, 2016, 44 (1), pp.103-115. ⟨10.1016/j.immuni.2015.12.007⟩. ⟨hal-01440246⟩