The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15
The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15
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DOI：
10.1016/j.immuni.2015.12.007
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发表时间：
2016-01-19
期刊：
影响因子：
32.4
通讯作者：
Huntington, Nicholas D.
中科院分区：
文献类型：
--
作者：
Delconte, Rebecca B.;Shi, Wei;Huntington, Nicholas D.
DNA结合抑制剂2（Id 2）是自然杀伤（NK）细胞发育所必需的，其典型作用是拮抗E蛋白功能和改变谱系命运。在这里，我们已经确定了一个关键的作用Id 2在调节白细胞介素-15（IL-15）受体信号和NK细胞的稳态通过抑制多个E蛋白靶基因，包括Socs 3。由于IL-15受体信号传导和代谢功能受损，成熟NK细胞中的Id 2缺失与其体内平衡不相容，这可以通过强IL-15受体刺激或Socs 3的遗传消融来挽救。在NK细胞成熟过程中，我们观察到E蛋白靶基因和Id 2之间的负相关性。这些结果改变了目前关于ID 2作用的范式，表明它不仅需要在NK细胞定型期间拮抗E蛋白，而且不断需要滴定E蛋白活性以调节NK细胞适应性和对IL-15的反应性。
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.