BCG and β-glucan primed monocytes yield dendritic cells that hamper the induction of pro-inflammatory T cell immunity

Dendritic cells (DCs) are professional antigen-presenting cells that regulate inflammatory and tolerogenic immunity. Their role within trained immunity, a process in which innate immune cells exhibit memory-like characteristics, remains to be elucidated. To date, increasing evidence indicates that trained immunity underlies the enhanced innate immune response induced by the Bacillus Calmette-Guérin (BCG) vaccine and the fungal cell wall component β-glucan (β-Glc), contributing to protection against heterologous infections and cancer. Concurrently, preclinical evidence suggests that BCG can also attenuate the severity of autoimmunity. Given the unclear immunomodulatory effects of these compounds on DCs we investigated the effects of BCG and β-Glc on human monocyte-derived DCs (moDCs). Our results demonstrate that early exposure to BCG and β-Glc during moDC development steers their function towards tolerance, indicated by reduced pro-inflammatory cytokine production upon rechallenge. Additionally, BCG and β-Glc challenge hampered the moDCs' ability to mount proinflammatory IFN-γ-driven T cell responses, while mediating the enrichment of regulatory T cells. Metabolically, we potentially observe signs that BCG amplifies glycolysis but not oxidative phosphorylation. Together, our findings provide novel insights into the role of BCG and β-Glc on human DCs and support the therapeutic potential of modulating human DCs with these training agents for the treatment of autoimmune disorders.