학술논문
IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development
Document Type
Article
Author
Goh, Wilford; Sudholz, Harrison; Foroutan, Momeneh; Scheer, Sebastian; Pfefferle, Aline; Delconte, Rebecca B.; Meng, Xiangpeng; Shen, Zihan; Hennessey, Robert; Kong, Isabella Y.; Schuster, Iona S.; Andoniou, Christopher E.; Davis, Melissa J.; Hediyeh-Zadeh, Soroor; Souza-Fonseca-Guimaraes, Fernando; Parish, Ian A.; Beavis, Paul; Thiele, Daniel; Chopin, Michael; Degli-Esposti, Mariapia A.; Cursons, Joe; Kallies, Axel; Rautela, Jai; Nutt, Stephen L.; Huntington, Nicholas D.
Source
Nature Immunology; February 2024, Vol. 25 Issue: 2 p240-255, 16p
Subject
Language
ISSN
15292908; 15292916
Abstract
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 Bcl2l11and 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 Ikzf1and Bcl2l11were 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 Ikzf1and Ikzf3in NK cells resulted in further reductions in Jun/Fosexpression 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.