Agent-specific training directs distinctive immune response against Listeria monocytogenes infection

The nonspecific protection provided by the innate immune system can be enhanced through training with stimuli, a phenomenon called 'trained immunity'. However, it remains unknown if distinct training programs with various functional outcomes can be induced. Here, we show that two training agents, flunisolide and myricetin, distinctively train and modulate the immune response against in vivo Listeria monocytogenes infection. Training with either agent led to significant reduction in pathogen burden but differed in the resulting immune functions. Training with myricetin led to the expansion of myeloid progenitor lineages, rapid cell recruitment, and enhanced phagocytosis. In contrast, training with flunisolide led to expansion of stem cell and multipotent progenitor populations, increase in antigen processing, and faster T cell expansion. We provide preliminary evidence that this divergent training outcomes may arise from agent-specific modulation of transcription factors. This study importantly shows that training can be directed at both the innate response and the onset of the adaptive response, highlighting the potential of modulating distinct training programs to influence protective immune responses.