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Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion


Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1,2,3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5,6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2−/− as compared to Irf2+/− mice. Irf2−/− HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2−/− HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN-α induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN–based therapies for viral infection and cancer.

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Figure 1: Reduction of functional HSCs in Irf2−/− mice.
Figure 2: Loss of Ifnar1 improves the reconstitution capacity of Irf2−/− HSCs.
Figure 3: Type I IFNs directly induce HSC proliferation.
Figure 4: Mechanisms underlying type I IFN–induced HSC proliferation.


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We thank Y. Abe and A. Obata-Onai for excellent animal care, K. Yamashita for experimental support, T.W. Mak (Campbell Family Institute for Breast Cancer Research, Toronto) and T. Taniguchi (the University of Tokyo) for the Irf2−/− mice and S. Taki (Shinshu University) for the Irf2−/−Ifnar1−/− mice. This work was supported in part by a Grant-in-Aid for Young Scientists (B) (to T. Sato), a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan (T.O.) and a Grant-in-Aid for the Global Center of Excellence (COE) Program.

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T. Sato conceived of the study, performed experiments, analyzed data and wrote the manuscript. N.O. assisted T. Sato with some of the experiments. H.Y. and F.A. performed Dynamic Array analysis. N.O., F.A., and T. Suda provided discussion and advice on some parts of study. T.O. supervised the overall project and wrote the manuscript.

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Correspondence to Toshiaki Ohteki.

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Sato, T., Onai, N., Yoshihara, H. et al. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion. Nat Med 15, 696–700 (2009).

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