The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia; Department of Computing and Information Systems, The University of Melbourne, VIC 3010, Australia.
Immunity. 2016 Jan 19;44(1):103-115. doi: 10.1016/j.immuni.2015.12.007. Epub 2016 Jan 12.
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.
DNA 结合抑制因子 2（Id2）对于自然杀伤（NK）细胞的发育至关重要，其典型作用是拮抗 E 蛋白的功能并改变谱系命运。在这里，我们发现 Id2 通过抑制多个 E 蛋白靶基因（包括 Socs3），在调节白细胞介素 15（IL-15）受体信号和 NK 细胞的稳态方面发挥着关键作用。由于 IL-15 受体信号和代谢功能受损，成熟 NK 细胞中的 Id2 缺失与它们的稳态不相容，这可以通过强烈的 IL-15 受体刺激或 Socs3 的基因缺失来挽救。在 NK 细胞成熟过程中，我们观察到 E 蛋白靶基因与 Id2 之间存在反比关系。这些结果改变了 ID2 作用的当前范例，表明它不仅需要在 NK 细胞承诺期间拮抗 E 蛋白，而且还需要不断调整 E 蛋白活性以调节 NK 细胞的适应性和对 IL-15 的反应性。
