先天性淋巴细胞
生物
淋巴细胞生成
细胞生物学
转录因子
免疫学
先天免疫系统
癌症研究
免疫系统
造血
遗传学
基因
干细胞
作者
Wilford Goh,Harrison Sudholz,Momeneh Foroutan,Sebastian Scheer,Aline Pfefferle,Rebecca B. Delconte,Xiangpeng Meng,Zihan Shen,Robert Hennessey,Isabella Y. Kong,Iona S. Schuster,Christopher E. Andoniou,Melissa J. Davis,Soroor Hediyeh-zadeh,Fernando Souza-Fonseca-Guimarães,Ian A. Parish,Paul A. Beavis,Daniel Thiele,Michaël Chopin,Mariapia A. Degli‐Esposti
标识
DOI:10.1038/s41590-023-01718-4
摘要
Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting in impaired interleukin-15 receptor signaling. Both Bcl2l11 and BIM levels, and intrinsic apoptosis were increased in Ikzf1-null NK cells, which in part accounts for NK lymphopenia as both were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with reduced AP-1 transcriptional complex expression and increased expression of Ikzf2/Helios and Ikzf3/Aiolos. IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in further reductions in Jun/Fos expression and complete loss of peripheral NK cells. Collectively, we show that Ikaros family members are important regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity. Ikaros, Helios and Aiolos are transcription factors involved in lymphocyte development. Here the authors dissect the regulatory role of these Ikaros family members to understand their contribution to NK cell development and functions.
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