BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

Cell Host Microbe. 2020 Aug 12;28(2):322-334.e5. doi: 10.1016/j.chom.2020.05.014. Epub 2020 Jun 15.

Abstract

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.

Trial registration: ClinicalTrials.gov NCT01906853.

Keywords: BCG; epigenetic imprinting; hematopoietic stem cells; monocyte; myeloid cell; myelopoiesis; trained immunity; vaccination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BCG Vaccine / immunology*
  • Bone Marrow / immunology
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Cytokines / metabolism
  • Female
  • Granulocytes / cytology*
  • Healthy Volunteers
  • Hematopoiesis / immunology*
  • Hematopoietic Stem Cells / cytology*
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Humans
  • Lipopolysaccharide Receptors / metabolism
  • Male
  • Monocytes / cytology*
  • Monocytes / immunology
  • Mycobacterium bovis / immunology
  • Transcription, Genetic / genetics
  • Transcriptome / genetics
  • Vaccination
  • Young Adult
  • alpha 1-Antitrypsin / blood

Substances

  • BCG Vaccine
  • CD14 protein, human
  • Cytokines
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Lipopolysaccharide Receptors
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin
  • Hepatocyte Nuclear Factor 1-beta

Associated data

  • ClinicalTrials.gov/NCT01906853