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Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation
Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden.
Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden.
Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden.
Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden.
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2019 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 49, no 9, p. 1344-1355Article in journal (Refereed) Published
Abstract [en]

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.

Place, publisher, year, edition, pages
2019. Vol. 49, no 9, p. 1344-1355
Keywords [en]
Aiolos, ILC, Ikaros, NK cells, lenalidomide
National Category
Immunology Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-390404DOI: 10.1002/eji.201848075ISI: 000483878000005PubMedID: 31151137OAI: oai:DiVA.org:uu-390404DiVA, id: diva2:1341672
Funder
Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Research CouncilSwedish Society for Medical Research (SSMF)Swedish Cancer SocietyAvailable from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-10-15Bibliographically approved

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