Programming innate immune memory: The context-dependent role of type I interferons

Type I interferons (IFNs) are best known for driving antiviral defense; however, a growing body of evidence identifies a pivotal role for type I IFNs in the establishment of innate immune memory. Depending on the nature of the priming stimulus, the identity of the responding cell, and the tissue microenvironment, type I IFN signaling may contribute to both trained immunity and tolerance. This review summarizes recent advances in identifying the molecular mechanisms by which the two best studied type I IFN family members, IFNα and IFNβ, contribute to innate immune memory. Stimuli triggering type I IFN expression range from microbial products and vaccines to inflammatory diseases, and result in reprogramming of hematopoietic stem and progenitor cells, monocytes/macrophages, dendritic cells and neutrophils. Mechanistically, type I IFNs contribute to the establishment of innate memory by remodeling chromatin accessibility and histone marks, reshaping metabolic pathways such as glycolysis, oxidative phosphorylation, lipid- and iron metabolism, and by reprogramming hematopoiesis and granulopoiesis. These effects provoke long-term immune adaptations in target cells that enhance or weaken their response to a subsequent challenge. We delineate parameters that contribute to the induction of trained immunity or tolerance and discuss potential translational implications. Ultimately, rigorous trials should test whether precise inhibition or exploitation of type I IFN signaling benefits patients by inducing or suppressing IFN-mediated innate immune memory, then using this context-specific framework to guide drug design, treatments and therapeutic endpoints.