A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity

Bacillus Calmette-Guerin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in hu-mans, and results in a more effective response of innate immune cells upon stimulation with heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8+ T cells show heterologous transcrip-tional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-g pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription fac-tors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon -related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.

Automated summary

BCG vaccination induces trained immunity in humans, resulting in an enhanced response of innate immune cells to different stimuli. Using single-cell RNA sequencing, this study investigates the heterogeneity of trained immunity induction by BCG vaccination. The findings reveal the diverse transcriptional responses of monocytes and CD8+ T cells and their active crosstalk, the critical role of the interferon-g pathway, and the important transcription factor STAT1. The study also highlights the relevance of type I interferon and neutrophil-related transcriptional programs in sepsis patients.