Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB⁺PD-1⁻ late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

第 2 组先天淋巴细胞 (ILC2) 是先天淋巴细胞的一个子集，可产生 2 型细胞因子，包括 IL-4、IL-5 和 IL-13。 GATA3 是 ILC2 多个阶段发育的关键转录因子。然而，GATA3 何时以及如何被诱导至 ILC2 发育所需的水平仍不清楚。在此，我们鉴定了ILC2特异性GATA3相关串联超级增强子（G3SE），其在ILC2定向前体中诱导高GATA3。 G3SE 缺陷小鼠在骨髓、肺、肝脏和小肠中表现出 ILC2 缺陷，对其他 ILC 谱系或 Th2 细胞的影响最小。单细胞 RNA 测序和随后的流式细胞术分析表明，进入 ILC2 阶段所需的 GATA3 诱导机制在 G3SE 缺陷小鼠的 IL-17RB ⁺ PD-1 ^-晚期 ILC2 前体阶段中丢失。 Cnot6l是 CCR4-NOT 去腺苷酶复合体的一部分，是 ILC2 发育过程中可能的 GATA3 靶标。我们的研究结果暗示了 ILC2 发育过程中 GATA3 表达的阶段特异性调节机制。