Immunology Department, Innate Immunity Unit, Institut Pasteur, 75724 Paris, France.
Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10240-5. doi: 10.1073/pnas.1217158110. Epub 2013 Jun 3.
Group 2 innate lymphoid cells (ILC2s; also called nuocytes, innate helper cells, or natural helper cells) provide protective immunity during helminth infection and play an important role in influenza-induced and allergic airway hyperreactivity. Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by ILC2s in response to IL-33 or -25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Here, we show that chimeric mice generated with Gata3-deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. In these chimeric mice, in vivo administration of IL-33 or -25 fails to expand ILC2 numbers or to induce characteristic ILC2-dependent IL-5 or -13 production. Moreover, cell-intrinsic Gata3 expression is required for ILC2 development in vitro and in vivo. Using mutant and transgenic mice in which Gata3 gene copy number is altered, we show that ILC2 generation from common lymphoid progenitors, as well as ILC2 homeostasis and cytokine production, is regulated by Gata3 expression levels in a dose-dependent fashion. Collectively, these results identify Gata3 as a critical early regulator of ILC2 development, thereby extending the paradigm of Gata3-dependent control of type 2 immunity to include both innate and adaptive lymphocytes.
组 2 先天淋巴细胞 (ILC2s；也称为 nuocytes、先天辅助细胞或自然辅助细胞) 在寄生虫感染期间提供保护性免疫，并在流感诱导和过敏性气道高反应性中发挥重要作用。转录因子 GATA 结合蛋白 3 (Gata3) 对于 ILC2s 在受到 IL-33 或 -25 刺激时产生 IL-5 和 -13 至关重要，但尚不清楚 Gata3 是否是 ILC2 从造血干细胞发育所必需的。在这里，我们表明，用 Gata3 缺陷型胎肝造血干细胞生成的嵌合小鼠不能系统地发育出 ILC2s。在这些嵌合小鼠中，体内给予 IL-33 或 -25 不能扩增 ILC2 数量或诱导特征性 ILC2 依赖性 IL-5 或 -13 产生。此外，细胞内固有 Gata3 表达对于体外和体内的 ILC2 发育是必需的。使用突变和转基因小鼠，其中 Gata3 基因拷贝数发生改变，我们表明，从共同淋巴祖细胞产生的 ILC2 以及 ILC2 稳态和细胞因子产生，受 Gata3 表达水平的调控，呈剂量依赖性。总之，这些结果确定 Gata3 是 ILC2 发育的关键早期调节剂，从而将 Gata3 依赖性 2 型免疫控制的范例扩展到包括先天和适应性淋巴细胞。
