UC San Diego

Epigenetic transcriptional memory, a heritable DNA modification enabling faster gene reactivation in response to environmental changes, has been extensively studied in cancer and immune cells. Approximately half of IFN-stimulated genes (ISGs) exhibit this memory. This study explored Type I IFN exposure in immune responses using an MX1-Cre-tdTomato mouse reporter model. In this model, IFN exposure led to genome rearrangement and permanent tdTomato expression, while IFN-naïve cells lacked tdTomato expression. By examining the percentage of tdTomato-expressing cells in immune lineages of unimmunized mice, we found that the majority of white blood cell (WBC) lineages in the blood contained within them populations that displayed IFN-experience, and this percentage increased with age. Upon in vitro stimulation, Type I IFN-experienced splenic natural killer (NK) cells showed enhanced activation marker upregulation, and splenic macrophages exhibited higher TNF-α secretion compared to IFN-naïve cells, suggesting heightened responsiveness due to prior IFN exposure. Further examination of gut microbiota manipulation effects on IFN experience and splenic cell activity showed that antibiotic treatment reduced tdTomato-expressing cells in blood, spleen, and bone marrow. In a germ-free (GF) mouse model colonized with bacteria inducing high or low tonic IFN signaling, augmented macrophage activity was observed in mice with bacteria inducing low IFN levels, but not in those with high IFN levels. These findings underscore the critical role of Type I IFN exposure in immune cell activation and function, while implicating gut microbiota in potentially controlling the level of IFN exposure and epigenetic memory that WBCs accumulate during homeostasis.