Department of Medical Research, National Taiwan University Hospital, Taipei 10002, Taiwan.
Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
Int J Mol Sci. 2021 Nov 11;22(22):12199. doi: 10.3390/ijms222212199.
The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.
转录因子 Ets1 是不变自然杀伤 T(iNKT)细胞在多个阶段发育/分化所必需的。然而，其在 iNKT 细胞中的作用机制和靶基因仍不清楚。在这里，我们表明 Ets1 是后选择胸腺 iNKT 细胞中最佳表达 Vα14Jα18 T 细胞受体(TCR)及其直接分化所必需的。Ets1 对于维持 iNKT 细胞的外周稳态也很关键，这是一个独立于 Vα14Jα18 TCR 表达的作用。对后选择 iNKT 细胞的全基因组转录组分析进一步揭示 Ets1 控制白细胞激活、增殖分化和白细胞介素介导的免疫。此外，Ets1 调节 iNKT 细胞中 ICOS 和 PLZF 的表达。更重要的是，恢复 PLZF 和 Vα14Jα18 TCR 的表达部分挽救了缺乏 Ets1 时 iNKT 细胞的分化。总之，我们的结果建立了一个详细的分子图谱，说明 Ets1 如何调节 iNKT 细胞的逐步分化。
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