Epigenetic Priming of Innate Immune Memory Following Vaccination
DOI:
https://doi.org/10.5281/zenodo.22761301Keywords:
trained immunity, BCG vaccination, monocyte, H3K4me3, H3K27ac, ATAC-seq, innate immune memory, epigenetic primingAbstract
Bacille Calmette-Guerin (BCG) vaccination induces a heterologous protective state termed trained immunity, in
which monocytes mount an enhanced cytokine response to unrelated infectious challenges for months after
vaccination, but the chromatin-level changes that persist after the acute response has resolved, and their
relationship to the enhanced phenotype, remain incompletely characterized at genome scale in humans. We
collected peripheral blood monocytes from 24 healthy volunteers before and at 2 weeks and 3 months after BCG
vaccination, and profiled H3K4me3 and H3K27ac by ChIP-seq and chromatin accessibility by ATAC-seq, paired
with ex vivo restimulation cytokine assays. At 3 months, when the acute response had fully resolved clinically,
monocytes retained significantly elevated H3K4me3 at 1,428 gene promoters relative to baseline, strongly enriched
near pattern recognition receptor and pro-inflammatory cytokine genes, with the magnitude of retention correlating
significantly with the magnitude of enhanced ex vivo tumor necrosis factor and interleukin-6 production upon
unrelated Staphylococcus aureus restimulation. ATAC-seq identified a largely overlapping set of 1,187 regions with
persistently increased accessibility at 3 months, concentrated at promoters and proximal enhancers rather than
distal elements. Pharmacological inhibition of the H3K4 methyltransferase SET7/9 during the first 72 hours after
BCG vaccination, applied in a parallel ex vivo training assay, prevented both persistent H3K4me3 and the
enhanced cytokine phenotype at the simulated 3-month time point without affecting the acute, 24-hour response,
indicating that SET7/9-dependent methylation deposited during an early priming window is specifically required for
the durability, rather than the initial establishment, of trained immunity. These results define a genome-wide
chromatin signature of human trained immunity persisting for at least three months after BCG vaccination and
identify a mechanistically necessary priming step underlying its durability.
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