Bacillus Calmette–Guérin-induced trained immunity potentiates TH17 responses in vitro

Trained immunity amplifies innate immune responses in an antigen-independent manner. This study explored the ability of trained human primary macrophages to modulate the phenotype and function of T cells. Macrophages play an important role in antigen presentation, resulting in T-cell activation and antigen-specific clonal expansion; however, few studies have investigated whether trained immunity induction in macrophages modulates T-cell activation. Here, through surface marker analysis of naive, β-glucan-, and Bacillus Calmette-Guérin-trained macrophages, we identified 8 distinct macrophage clusters following trained immunity induction. One of these populations showed an increase in surface activation markers CD40 and CD86, as well as major histocompatibility complex molecules. In vitro co-culture of T cells with autologous Bacillus Calmette-Guérin-trained macrophages resulted in a skewing toward TH17 cells. We also observed an increase in TH17 percentage after Bacillus Calmette-Guérin vaccination of human subjects. The bias toward TH17 triggered by trained macrophages required direct T cell to macrophage contact. Trained macrophages potentiated TH17 skewing independently of the antigen presented. While co-cultures of T cells and Bacillus Calmette-Guérin-trained macrophages responded with higher production of interferon-γ and interleukin-17 after stimulation, no clear shifts toward effector or memory T cells were observed. In conclusion, this study provides evidence that Bacillus Calmette-Guérin-trained macrophages can modulate T-cell function toward a TH17 phenotype, suggesting that Bacillus Calmette-Guérin-induced trained immunity has the potential to enhance not only innate immune responses but also to modify adaptive T-cell immunity.