Human Bacille Calmette-Guérin Vaccination Elicits Trained Immunity Via the Hematopoietic Progenitor Compartment

Abstract

Induction of trained immunity by Bacille-Calmette-Guerin (BCG) vaccination mediates beneficial heterologous effects, but the underlying mechanisms regulating the longevity and magnitude of such effects remain elusive. We show that BCG vaccination in humans induces the long-lasting activation of a transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell compartment in the bone marrow. As crucial regulators of this transcriptional shift we identify hepatic nuclear factor family members 1a and b. These findings are corroborated by higher granulocyte numbers in BCG- vaccinated infants, HNF1 SNP variants correlating with trained immunity, and elevated serum concentrations of the HNF1 target gene SERPINA1. In addition, transcriptomic HSPC remodelling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature 3 months after BCG vaccination. Taken together, transcriptomic, epigenomic and functional reprogramming of HSPCs and peripheral monocytes is pivotal in human in vivo BCG-induced trained immunity.