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Innate immunity

Train your histones

Nature Immunology volume 26, page 983 (2025)Cite this article

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Previous cellular experiences can be remembered by epigenetic modifications of chromatin, which can then promote or impair subsequent cellular responses. This epigenetic memory process underlies the concept of ‘trained immunity’ that occurs in innate immune cells. In Cell, Ziogas et al. show that monocytes from humans vaccinated with Bacille Calmette-Guérin (BCG) undergo long-term epigenetic reprogramming that involves histone H3 lactylation on lysine 18 (H3K18la). BCG-induced training increases intracellular lactate production, in part by increasing expression of PKM, LDHA and LDHB. After BCG stimulation, the chromatin modifier p300–CBP promotes H3K18la post-translational modifications, which mainly occur at distal enhancers — in particular, at loci enriched for bZIP transcription factor motifs and CTCF-binding sites. Notably, this response seems to rely on intracellular lactate sources. This H3K18la memory response is associated with increased cytokine and chemokine gene expression that can persist for months after initial stimulation. These findings provide mechanistic underpinnings for the BCG-mediated trained immune effects.

Original reference: Cell 188, 2992–3012 (2025)

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  1. Nature Immunology https://www.nature.com/ni/

    Laurie A. Dempsey

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  1. Laurie A. Dempsey
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Correspondence to Laurie A. Dempsey.

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Dempsey, L.A. Train your histones. Nat Immunol 26, 983 (2025). https://doi.org/10.1038/s41590-025-02214-7

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