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.
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Acknowledgements
We thank the N.D.H. laboratory members A. Doan and T. Camilleri for technical assistance and animal husbandry. We extend our gratitude to Monash University platform staff and administration for their services. We are extremely grateful to M. Busslinger (IMP, Austria) for providing the Ikzf1loxP mice, E. Vivier (CIML, France) for providing the Ncr1iCre mice, M. Caligiuri (City of Hope, USA) for providing the Il15Tg and F. Ishikawa (RIKEN, Japan) for providing the human IL-15/IL-7 transgenic NSG mice and D. Lee (Nationwide Children’s Hospital, USA) for the K562-CSTX002 cell line. W.G. was supported by a Melbourne International Research Scholarship. M.F. was supported by an Investigator Fellowship from the Prostate Cancer Foundation (USA). This work is supported by project grants from the NHMRC of Australia (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472 and GNT1184615 to N.D.H.) and an NHMRC Investigator Fellowship (GNT1195296 to N.D.H.). N.D.H. is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust, Melanoma Research Alliance Young Investigator Award, an Ian Potter Foundation equipment grant, the National Foundation for Medical Research and Innovation (NFMRI) John Dixon Hughes Medal, and a CLIP grant from the Cancer Research Institute. S.L.N. is an NHMRC SPRF Fellow (GNT1155342). M.A.D.-E. is an NHMRC PRF Fellow (GNT1119298). J.R. was supported by a Victorian Cancer Agency grant (ECSG18020).
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W.G., S.S., H.S., Z.S., A.P., R.H., I.K., R.B.D., C.E.A., I.S.S., P.B., D.T., I.P., M.C., X.M., F.S.-F.-G and J.R. designed and performed experiments. M.F., S.H.-Z. and S.S. provided bioinformatics analysis and input into interpretation of results. N.D.H., S.L.N., M.J.D., J.C., J.R., A.K. and M.A.D.-E. supervised experimental design and provided input into interpretation of results. S.L.N., A.K. and N.D.H. wrote the manuscript with editorial input from all authors.
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N.D.H. and J.R. are founders and shareholders in oNKo-Innate. N.D.H. is an inventor on patents relating to this work. N.D.H. serves on an advisory board for Bristol Myers Squibb. The other authors declare no competing interests.
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Goh, W., Sudholz, H., Foroutan, M. et al. IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development. Nat Immunol 25, 240–255 (2024). https://doi.org/10.1038/s41590-023-01718-4
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DOI: https://doi.org/10.1038/s41590-023-01718-4