TY - JOUR
T1 - IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development
AU - Goh, Wilford
AU - Sudholz, Harrison
AU - Foroutan, Momeneh
AU - Scheer, Sebastian
AU - Pfefferle, Aline
AU - Delconte, Rebecca B.
AU - Meng, Xiangpeng
AU - Shen, Zihan
AU - Hennessey, Robert
AU - Kong, Isabella Y.
AU - Schuster, Iona S.
AU - Andoniou, Christopher E.
AU - Davis, Melissa J.
AU - Hediyeh-Zadeh, Soroor
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Parish, Ian A.
AU - Beavis, Paul
AU - Thiele, Daniel
AU - Chopin, Michael
AU - Degli-Esposti, Mariapia A.
AU - Cursons, Joe
AU - Kallies, Axel
AU - Rautela, Jai
AU - Nutt, Stephen L.
AU - Huntington, Nicholas D.
N1 - Publisher Copyright:
© 2024, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85181464887
UR - https://pubmed.ncbi.nlm.nih.gov/38182668
U2 - 10.1038/s41590-023-01718-4
DO - 10.1038/s41590-023-01718-4
M3 - Article
C2 - 38182668
AN - SCOPUS:85181464887
SN - 1529-2908
VL - 25
SP - 240
EP - 255
JO - Nature Immunology
JF - Nature Immunology
IS - 2
ER -