The epigenetic adaptation of innate immune cells to inflammatory stimuli, or trained immunity, represents an evolutionarily conserved feature of host defense. Recent advances have revealed that such adaptations can occur at the level of hematopoietic stem and progenitor cells, resulting in long-lasting epigenetic reprogramming of the immune system. However, a comprehensive mechanistic understanding of these processes remains incomplete, limiting our capacity to predict or therapeutically manipulate the adaptive capacity of hematopoiesis. In this review, we survey the current literature to support a model of hematopoietic memory whose stimulus-specific nuances are shaped by specific cytokine environments and driven by the combinatorial activity of key transcription factors. Comparative analyses underscore the evolutionary conservation and essential biological roles of these factors, suggesting that trained immunity may reflect the strategic repurposing of ancient transcriptional programs for the purpose of enhancing host defense.
