After activation, some invariant natural killer T (iNKT) cells are differentiated into Klrg1⁺ long-lived effector NKT1 cells. However, the regulation from the effector phase to the memory phase has not been elucidated. Zeb2 is a zinc finger E homeobox-binding transcription factor and is expressed in a variety of immune cells, but its function in iNKT cell differentiation remains also unknown. Here, we show that Zeb2 is dispensable for development of iNKT cells in the thymus and their maintenance in steady state peripheral tissues. After ligand stimulation, Zeb2 plays essential roles in the differentiation to and maintenance of Klrg1⁺ Cx3cr1⁺GzmA⁺ iNKT cell population derived from the NKT1 subset. Our results including single-cell-RNA-seq analysis indicate that Zeb2 regulates Klrg1⁺ long-lived iNKT cell differentiation by preventing apoptosis. Collectively, this study reveals the crucial transcriptional regulation by Zeb2 in establishment of the memory iNKT phase through driving differentiation of Klrg1⁺ Cx3cr1⁺GzmA⁺ iNKT population.

激活后，一些不变的自然杀伤 T (iNKT) 细胞分化为 Klrg1 ⁺长寿命效应 NKT1 细胞。然而，从效应阶段到记忆阶段的调节尚未阐明。Zeb2是一种锌指E同源盒结合转录因子，在多种免疫细胞中表达，但其在iNKT细胞分化中的功能仍不清楚。在这里，我们证明 Zeb2 对于胸腺中 iNKT 细胞的发育及其在稳态外周组织中的维持是不可或缺的。配体刺激后，Zeb2在源自 NKT1 亚群的Klrg1 ⁺ Cx3cr1 ⁺ GzmA ⁺ iNKT 细胞群的分化和维持中发挥重要作用。我们的结果（包括单细胞 RNA-seq 分析）表明 Zeb2 通过防止细胞凋亡来调节 Klrg1 ⁺长寿命 iNKT 细胞分化。^{总的来说，这项研究揭示了 Zeb2 通过驱动 Klrg1 +} Cx3cr1 ⁺ GzmA ⁺ iNKT 群体的分化在记忆 iNKT 阶段建立中的关键转录调控。