IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development

Wilford Goh, Harrison Sudholz (Main author), Momeneh Foroutan (Main author), Sebastian Scheer (Main author), 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-Guimaraes, Ian A. Parish, Paul Beavis, Daniel Thiele, Michael Chopin, Mariapia A. Degli-EspostiJoe Cursons, Axel Kallies, Jai Rautela, Stephen L. Nutt, Nicholas D. Huntington*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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 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.

Original languageEnglish
Pages (from-to)240-255
Number of pages16
JournalNature Immunology
Volume25
Issue number2
Early online date5 Jan 2024
DOIs
Publication statusPublished - Feb 2024

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