IRF8 Regulates Cell Cycle of Hematopoietic Stem Cells

IRF8 is expressed predominately in hematopoietic cells as a transcription factor and regulator of innate immune receptors signaling. It plays a critical role in the development of innate immune and adaptive immune cells, including dendritic cells, monocytes, eosinophils, basophils, B and T lymphocytes. It also functions as a tumor suppressor, as IRF8 deficient mice manifest a chronic myelogenous leukemia (CML)-like syndrome. In addition to various lineages of hematopoietic cells, we have found that IRF8 is expressed in hematopoietic stem cells (HSCs). However, the function of IRF8 in HSCs was unknown. In this study we investigated the role of IRF8 in regulating HSCs. We found that the number of long-term (LT)-HSCs (Lin^- Sca1⁺ c-Kit⁺ CD48^- CD150⁺) is significantly reduced in IRF8 knockout mice (IRF8^-/-), comparing to the wild-type (WT) controls. Long-term reconstitution assays showed that IRF8^-/- LT-HSC's repopulation capability is severely impaired compared to equal amount of WT mouse LT-HSCs. The effect of IRF8 depletion on HSC's self-renewal capacity is unlikely due to the influence of the CML-like syndrome, since the disease is not transplantable and only seen in the primary mice. In addition, the number of LT-HSCs is also decreased in E14.5 fetal liver of IRF8^-/- mice, when the myeloproliferative disorder has not been manifested. A cell cycle analysis showed that the number of LT-HSCs in S, G2 or M phase is greatly reduced in IRF8^-/- mice comparing to that in WT mice. Transcription profiling analysis of LT-HSCs revealed that the expression of key regulators of cytokine/growth factor signaling and factors controlling HSC self-renewal are downregulated in IRF8^-/- mice comparing to that in WT mice. These results indicate that IRF8 plays a critical role in regulating cell cycle entry of HSCs. This function of IRF8 may play an important role in activating HSCs to enhance immunity and innate immunity.