Innate Immunity Unit, Inserm U668, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
Cell Rep. 2015 Mar 31;10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057. Epub 2015 Mar 19.
Innate lymphoid cells (ILCs) are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. Here, we show that NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP). Cell-intrinsic Nfil3 ablation led to variably impaired development of fetal and adult ILC subsets. Conditional gene targeting demonstrated that NFIL3 exerted its function prior to ILC subset commitment. Accordingly, NFIL3 ablation resulted in loss of ID2(+) CHILP and PLZF(+) ILC progenitors. Nfil3 expression in lymphoid progenitors was under the control of the mesenchyme-derived hematopoietin IL-7, and NFIL3 exerted its function via direct Id2 regulation in the CHILP. Moreover, ectopic Id2 expression in Nfil3-null precursors rescued defective ILC lineage development in vivo. Our data establish NFIL3 as a key regulator of common helper-like ILC progenitors as they emerge during early lymphopoiesis.
先天淋巴细胞 (ILC) 是一类效应细胞，起源于共同的先天淋巴细胞祖细胞。然而，决定 ILC 谱系身份的转录程序仍然难以捉摸。在这里，我们表明 NFIL3 是共同辅助样先天淋巴细胞祖细胞 (CHILP) 的关键调节因子。细胞内 Nfil3 缺失导致胎儿和成年 ILC 亚群的发育不同程度受损。条件性基因靶向表明 NFIL3 在 ILC 亚群承诺之前发挥其功能。因此，NFIL3 缺失导致 ID2(+)CHILP 和 PLZF(+)ILC 祖细胞的丧失。淋巴祖细胞中 Nfil3 的表达受间质衍生的造血细胞因子 IL-7 的控制，NFIL3 通过在 CHILP 中直接调节 Id2 发挥其功能。此外，NFIL3 缺陷前体中的异位 Id2 表达挽救了体内缺陷 ILC 谱系发育。我们的数据确立了 NFIL3 作为共同辅助样 ILC 祖细胞在早期淋巴发生过程中出现的关键调节因子。
