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Iron metabolism

Ironman training for NK cells

Nature Immunology volume 24, pages 1599–1601 (2023)Cite this article

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IRF4 is required for the differentiation of T cells, B cells and some myeloid cells. A new study finds that IRF4 is upregulated following natural killer (NK) cell activation and is required for the differentiation and expansion of virus-specific NK cells by controlling nutrient acquisition, including iron uptake.

Several IRF family members, such as IRF4, IRF7 and IRF8, are induced in NK cells in response to MCMV, with IRF4 levels peaking three days following infection, consistent with the kinetics of induction by interferon. However, interferon-α (IFNα) alone was not adequate to induce IRF4 in NK cells in vitro, whereas induction of IRF8 and IRF9 is primarily dependent on the interleukin-12 (IL-12)–STAT4 and type I interferon–STAT1 signaling. Assay of transposase-accessible chromatin with sequencing (ATAC–seq) analysis of highly accessible regions demonstrated that recognition motifs for IRF4, AP-1 and the IRF basic leucine zipper domain (TGA(C/G)TCA; also known as AP-1–IRF composite elements (AICEs)) are enriched four days after MCMV infection, suggesting cooperation between IRF4 and AP-1 family members. Specifically, regions that are accessible to the AP-1 family members BATF and JUN were significantly enriched from days two to four after infection, hinting at key roles for AICEs in target genes in the NK cell response to MCMV (Fig. 1). These data complement the group’s previous findings that IRF8 was required for virus-specific NK cell expansion and innate memory generation; mechanistically, IRF8 directly regulated expression of ZBTB32, a transcription factor essential for the virus-specific NK cell proliferative burst3. Indeed, ZBTB32 contains an AP-1 binding motif, supporting its regulation by IRF8–AP-1 complexes. However, ZBTB32 was not flagged as being differentially expressed in Irf4−/− NK cells during MCMV infection, highlighting divergent essential roles for IRF8–AP-1 and IRF4–AP-1 complexes in NK cell-mediated viral immunity. The role of AP-1 members in regulating NK cell biology remains enigmatic and these new data underscore a need for further research into regulators of AP-1 transcription factors and their targets.

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Fig. 1: How iron uptake determines NK cell function.

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Acknowledgements

N.D.H. is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472 and GNT1184615) and an NHMRC Investigator Fellowship (GNT1195296).

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  1. Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

    Nicholas D. Huntington

  2. oNKo-Innate, Moonee Ponds, Victoria, Australia

    Nicholas D. Huntington

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Correspondence to Nicholas D. Huntington.

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N.D.H. reports stock or other ownership in oNKo-Innate, serves on an advisory board for Bristol Myers Squibb and is an inventor on multiple licensed patents concerning cytokine checkpoints in NK cell therapies and IL-15 receptor agonists.

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Huntington, N.D. Ironman training for NK cells. Nat Immunol 24, 1599–1601 (2023). https://doi.org/10.1038/s41590-023-01626-7

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