iNKT subsets differ in their developmental and functional requirements on Foxo1
iNKT subsets differ in their developmental and functional requirements on Foxo1
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iNKT 子集对 Foxo1 的发育和功能要求不同
DOI：
10.1073/pnas.210595011811
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发表时间：
2021-11-16
影响因子：
11.1
通讯作者：
Bai，Li
中科院分区：
文献类型：
--
作者：
Zhang，Huimin;Zhang，Yuwei;Bai，Li
不变性自然杀伤T细胞（iNKT）在调节免疫应答中起着重要作用。基于细胞因子谱和关键转录因子，iNKT细胞可分为iNKT1、iNKT2和iNKT17亚群。然而，这些亚群的发育和功能是否受到不同机制的控制尚不清楚。在这里，我们发现叉头盒蛋白O1 （Foxo1）促进iNKT1和iNKT2细胞的分化，而不是iNKT17细胞，因为它在这些亚群中对IL7R表达有不同的贡献。在iNKT1和iNKT2细胞分化的早期阶段，细胞核Foxo1对il7的表达至关重要，但在iNKT17细胞中则是必不可少的。在iNKT17细胞中，rorγ - t代替Foxo1促进IL7R的表达。此外，iNKT1和iNKT2细胞的效应功能需要Foxo1，而iNKT17细胞不需要Foxo1。细胞质Foxo1通过抑制TSC1-TSC2相互作用促进iNKT1和iNKT2细胞中mTORC1的激活，而iNKT17细胞中mTORC1的激活是必不可少的。iNKT17细胞表现出与iNKT1和iNKT2细胞不同的代谢基因表达模式，这与iNKT1和iNKT2细胞对Foxo1的不同功能需求相匹配。总之，我们的研究结果表明，iNKT细胞亚群在Foxo1的发育和功能需求上存在差异。
Invariant natural killer T (iNKT) cells play important roles in regulating immune responses. Based on cytokine profiling and key transcriptional factors, iNKT cells are classified into iNKT1, iNKT2, and iNKT17 subsets. However, whether the development and functions of these subsets are controlled by distinct mechanisms remains unclear. Here, we show that forkhead box protein O1 (Foxo1) promotes differentiation of iNKT1 and iNKT2 cells but not iNKT17 cells because of its distinct contributions to IL7R expression in these subsets. Nuclear Foxo1 is essential forIl7rexpression in iNKT1 and iNKT2 cells at early stages of differentiation but is dispensable in iNKT17 cells. RORγt, instead of Foxo1, promotes IL7R expression in iNKT17 cells. Additionally, Foxo1 is required for the effector function of iNKT1 and iNKT2 cells but not iNKT17 cells. Cytoplasmic Foxo1 promotes activation of mTORC1 in iNKT1 and iNKT2 cells through inhibiting TSC1–TSC2 interaction, whereas it is dispensable for mTORC1 activation in iNKT17 cells. iNKT17 cells display distinct metabolic gene expression patterns from iNKT1 and iNKT2 cells that match their different functional requirements on Foxo1. Together, our results demonstrate that iNKT cell subsets differ in their developmental and functional requirements on Foxo1.