Metabolic–Epigenetic Rewiring of CCR5 hi Monocytes Sustains Long-Term Trained Immunity Against Lethal Sepsis [CUT&Tag]

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that co-immunization with Bacillus Calmette–Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG+BLP vaccination activated the AKT–mTOR–HIF-1α axis, driving glycolytic reprogramming and subsequent lactate accumulation. We found that elevated lactate then promoted KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. Critically, CCR5hi monocytes isolated from vaccinated human cord blood recapitulated these lactate-driven lactylation and trained immunity features. Together, our findings define a novel lactate–KAT2B–H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5hi monocytes, highlighting CCR5hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis