Irf8 Regulates Cytokine Signaling and Proliferation of Hematopoietic Stem Cells

Irf8 is a member of the Interferon Regulatory Factor family, playing diverse functions in the development of innate and adaptive immune cells and in defenses against intracellular pathogens. We found, for the first time, that the loss of Irf8 results in a severe decrease in number and the reconstitution capacity of long-term hematopoietic stem cells (LT-HSCs). The fact that Irf8deficient hematopoietic microenvironment did not affect the reconstitution ability of HSCs indicates that Irf8 regulates HSCs in a cell autonomous manner. The effect of Irf8 depletion on HSC's number and the reconstitution capacity is unlikely due to the influence of a myeloproliferative syndrome, as the disease is not transplantable. In addition, the number of LT-HSCs is also decreased in E14.5 fetal liver of Irf8deficient mice, when the myeloproliferative disorder has not been developed. A cell cycle analysis show that the number of cycling LT-HSCs is greatly reduced in Irf8deficient mice. In addition, LT-HSCs in Irf8deficient mice failed to enter cell cycle in response to the interferon treatment. Genome-wide transcription profiling and activity of cis-regulatory element analysis of LT-HSCs reveal that the expression of key regulators of cytokine/growth factor signaling and factors controlling HSC self-renewal are dysregulated in Irf8deficient mice. These results indicate that Irf8 plays a critical role in regulating cytokine signaling and cell cycle of HSCs and that Irf8 plays an orchestrated role in enhancing innate and adaptive immunity starting from the top of hematopoietic hierarchy.