Exosomal CLOCK-stabilizing lncRNA confers innate memory in tuberculosis resisters [RNAseq]

Innate immune cells develop enhanced responsiveness to secondary challenges through trained immunity, a process reliant on memory of prior encounters. However, the intercellular regulatory mechanisms and mediators dictating host-protective trained immunity against infections remain incompletely understood. By profiling plasma exosomal long non-coding RNA (lncRNA) repertoires in a tuberculosis (TB) resister cohort resistant to Mycobacterium tuberculosis (Mtb) infection, we identify lncRNA TB Resister-derived CLOCK Regulator 1 (TRCR1) as an immune trainer for monocytes during their differentiation into macrophages. Mechanistically, internalized exosomal TRCR1 collaborates with RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming condensed lncRNA-protein-mRNA complexes in the cytosol, thereby facilitating the expression of CLOCK, a circadian regulator with histone acetyltransferase activity. This upregulated CLOCK amplifies histone H3 acetylation (K9/K14) at promoters of cytokine-encoding and autophagy-related genes, establishing epigenetic memory in monocytes. We further demonstrate that Mtb-secreted antigens induce human lung epithelial cells to release TRCR1-enriched exosomes, which educate monocytes to develop augmented antimicrobial capacity. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular immune training axis wherein exosomal TRCR1 orchestrates CLOCK-mediated epigenetic programming to potentiate innate memory, providing a strategy for refining BCG vaccination and preventing infectious diseases.