The natural killer (NK) and non-cytotoxic innate lymphoid cells (ILC) lineages play vital role in the regulation of the immune system. Yet understanding of mechanisms controlling NK/ILC development remains incomplete. The evolutionary conserved FOXO family of forkhead transcription factors are critical regulators of cellular processes. We found that the loss of FOXO1 and FOXO3 together caused impaired activation of the NK gene expression program and reduced ETS binding already at the common lymphoid progenitor (CLP) level and a block at the ILC progenitor (ILCP) to NK progenitor transition. FOXO controlled NK cell maturation in organ specific manner and their ability to respond to IL-15. At the ILCP level, disruption of the ILC lineage specific gene programs was associated with broad perturbation of the generation of the non-cytotoxic ILC subsets. We concluded that FOXO1 and FOXO3 cooperatively regulate ILC lineage specification at the progenitor level as well as the generation of mature ILCs.

中文翻译：

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FOXO1和FOXO3协同调节先天性淋巴样细胞发育

天然杀手（NK）和非细胞毒性先天淋巴样细胞（ILC）谱系在调节免疫系统中起着至关重要的作用。然而，对控制NK / ILC发展的机制的理解仍然不完整。叉头转录因子的进化保守FOXO家族是细胞过程的关键调节因子。我们发现，FOXO1和FOXO3的缺失共同导致NK基因表达程序的激活受损，并降低了常见淋巴祖细胞（CLP）水平的ETS结合力，以及ILC祖细胞（ILCP）向NK祖细胞转变的阻滞作用。FOXO以器官特异性方式及其对IL-15的反应能力控制NK细胞的成熟。在ILCP水平，ILC谱系特异性基因程序的破坏与非细胞毒性ILC亚群的产生的广泛扰动有关。