Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Biomedical Research Center, Chiba University, Chiba, Japan.
Nat Commun. 2024 Jul 5;15(1):5610. doi: 10.1038/s41467-024-49881-y.
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-17RBPD-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.
2 型固有淋巴细胞 (ILC2) 是固有淋巴细胞的一个亚群，能够产生 2 型细胞因子，包括 IL-4、IL-5 和 IL-13。GATA3 是 ILC2 在多个阶段发育所必需的关键转录因子。然而，GATA3 何时以及如何被诱导到 ILC2 发育所需的水平尚不清楚。在此，我们鉴定了 ILC2 特异性 GATA3 相关串联超级增强子 (G3SE)，它可诱导 ILC2 前体细胞中高水平的 GATA3。G3SE 缺陷小鼠的骨髓、肺、肝和小肠中 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，G3SE 缺陷小鼠中，进入 ILC2 阶段所需的 GATA3 诱导机制在晚期 ILC2 前体细胞阶段丢失。CCR4-NOT 脱腺苷酸酶复合物的一部分 Cnot6l 可能是 ILC2 发育过程中 GATA3 的一个潜在靶标。我们的研究结果表明，在 ILC2 发育过程中，GATA3 的表达存在一个特定阶段的调控机制。
