Interferon responsiveness reporter mice demonstrate memory of interferon exposure by hematopoietic stem progenitor cells 3091

Abstract Description Trained immunity occurs after an inflammatory reaction induces epigenetic changes in innate immune cells, leading to altered responses upon subsequent. The innate cells that might adapt during trained immunity include natural killer (NK) cells, monocytes/macrophages, and even hematopoietic stem progenitor cells (HSPCs). To track interferon (IFN) exposure, we used MX1-CRE mice, which induce the Cre recombinase upon exposure to Type I IFN, we track and lineage trace IFN-experience with an LSL-tdTRed (TR) reporter transgene. In these dual transgenic mice, IFN-exposed cells permanently express TR, allowing for easy tracking. IFN-naïve cells in the mice remain unlabeled. We found that hematopoietic stem progenitor cells (HSPCs) had IFN-exposure even without an inflammatory stimulus, consistent with the role of IFN in hematopoiesis. Notably, the exposure of HSPCs to IFN seemed to be “remembered” by their TR-labeled progeny. Specifically natural killer (NK) cells and macrophages descended from TR-expressing HSPCs (IFN-experienced) had greater activity than their IFN-naïve counterparts from the same animal. We further demonstrate that the microbiome could impact on the levels of IFN-experienced cells. Gene expression studies define a unique signature for IFN experience in NK and macrophage lineages. We conclude that HSPCs may “remember” exposure to IFN during normal hematopoiesis and pass this memory to their descendants, leading to altered activities. Funding Sources The Hartwell Foundation Topic Categories Hematopoiesis and Immune System Development (HEM)