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

Nature Immunology volume 25, pages 240–255 (2024)Cite this article

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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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Fig. 1: Conditional deletion of Ikaros leads to NK lymphopenia.
Fig. 2: Defective NK cell immunity in Ikzf1Δ/Δ mice.
Fig. 3: Impaired IL-15 signaling and survival in the absence of Ikzf1.
Fig. 4: Ikaros directly regulates genes controlling lineage fate, cytokine signaling and apoptosis in NK cells.
Fig. 5: Loss of both Ikaros and Aiolos is incompatible with NK cell development.
Fig. 6: Aiolos and Ikaros target overlapping genes essential for innate lymphopoiesis.
Fig. 7: Ikaros and Aiolos directly activate AP-1 transcription factors.
Fig. 8: Human NK cells require Ikaros family members for optimal function.

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Data availability

RNA-seq, ChIP–seq, CUT&RUN and ATAC-seq data are publicly available at the Gene Expression Omnibus under accession codes GSE247283, GSE13229, GSE113031 and GSE230035.

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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).

Author information

Author notes

  1. These authors contributed equally: Wilford Goh, Harrison Sudholz, Momeneh Foroutan, Sebastian Scheer, Aline Pfefferle.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research. Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia

    Wilford Goh, Rebecca B. Delconte, Robert Hennessey, Isabella Y. Kong, Melissa J. Davis, Soroor Hediyeh-Zadeh & Stephen L. Nutt

  2. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Harrison Sudholz, Momeneh Foroutan, Sebastian Scheer, Aline Pfefferle, Xiangpeng Meng, Zihan Shen, Robert Hennessey, Daniel Thiele, Michael Chopin, Joe Cursons, Jai Rautela & Nicholas D. Huntington

  3. oNKo-Innate Pty Ltd, Melbourne, Victoria, Australia

    Momeneh Foroutan, Aline Pfefferle, Joe Cursons, Jai Rautela & Nicholas D. Huntington

  4. Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

    Sebastian Scheer

  5. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Rebecca B. Delconte

  6. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Iona S. Schuster, Christopher E. Andoniou & Mariapia A. Degli-Esposti

  7. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia

    Iona S. Schuster, Christopher E. Andoniou & Mariapia A. Degli-Esposti

  8. Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia

    Melissa J. Davis & Fernando Souza-Fonseca-Guimaraes

  9. The South Australian immunoGENomics Cancer Institute (SAiGENCI), Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia

    Melissa J. Davis

  10. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Ian A. Parish & Paul Beavis

  11. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Ian A. Parish & Paul Beavis

  12. Department of Microbiology & Immunology, Faculty of Medicine, Dentistry and Health Sciences & Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    Axel Kallies

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Contributions

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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Correspondence to Nicholas D. Huntington.

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Competing interests

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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