The impact of interferon-γ pathway on trained immunity induction by vaccination with Bacille Calmette-Guérin

Bacillus Calmette-Guérin (BCG) has multiple heterologous off-target effects which extend beyond tuberculosis (TB) prophylaxis, which include protection against other non-tuberculous infections, autoimmune diseases, and tumor development. These heterologous effects are at least partially mediated by induction of trained immunity. In this study, we aimed to investigate the impact of IFNγ production capacity on induction of trained immunity in human volunteers vaccinated with BCG. We evaluated inflammation and immune activation-specific cytokine responses (IFNγ, TNF, IL-1, and IL-6) in PBMCs isolated from 323 healthy volunteers vaccinated with BCG and stimulated with either Mycobacterium tuberculosis or Staphylococcus aureus. We further assessed the impact of genetic variants in genes crucial for the biological activity of IFNγ pathway on trained immunity using single nucleotide polymorphism (SNP) genotyping. We found a significant correlation between baseline IFNγ production capacity and induction of trained immunity, as assessed by the fold-change increase in IL-6 production at both day 14 and day 90 post-vaccination compared to production before vaccination. A similar correlation was found between basal IFNγ production and increased IL-1β production at day 14 after BCG. This suggests that individuals with higher IFNγ production capacity exhibit stronger trained immunity responses post-BCG vaccination. This hypothesis is supported by the finding that SNPs in genes involved in the IFNγ biological pathway significantly influence trained immunity responses in humans. IFNγ production capacity and genetic variations in the IFNγ pathway genes impact the magnitude of trained immunity response, providing insights into the regulation of innate memory responses.