A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity
Wenchao Li, Simone J.C.F.M. Moorlag, Valerie A. C. M. Koeken, Rutger J. Röring, L. Charlotte J. de Bree, Vera P. Mourits, Manoj Kumar Gupta, Bowen Zhang, Jianbo Fu, Zhenhua Zhang, Inge Grondman, Krista E. van Meijgaarden, Liang Zhou, Ahmed Alaswad, Leo A. B. Joosten, Reinout van Crevel, Cheng‐Jian Xu, Mihai G. Netea, Yang Li
Abstract
Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, 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 transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ 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 factors 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.