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Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection

Abstract

Lymphocytes and neutrophils are rapidly depleted by systemic infection1. Progenitor cells of the haematopoietic system, such as common myeloid progenitors and common lymphoid progenitors, increase the production of immune cells to restore and maintain homeostasis during chronic infection, but the contribution of haematopoietic stem cells (HSCs) to this process is largely unknown2. Here we show, using an in vivo mouse model of Mycobacterium avium infection, that an increased proportion of long-term repopulating HSCs proliferate during M. avium infection, and that this response requires interferon-γ (IFN-γ) but not interferon-α (IFN-α) signalling. Thus, the haematopoietic response to chronic bacterial infection involves the activation not only of intermediate blood progenitors but of long-term repopulating HSCs as well. IFN-γ is sufficient to promote long-term repopulating HSC proliferation in vivo; furthermore, HSCs from IFN-γ-deficient mice have a lower proliferative rate, indicating that baseline IFN-γ tone regulates HSC activity. These findings implicate IFN-γ both as a regulator of HSCs during homeostasis and under conditions of infectious stress. Our studies contribute to a deeper understanding of haematological responses in patients with chronic infections such as HIV/AIDS or tuberculosis3,4,5.

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Figure 1: Infection with Mycobacterium avium induces changes in haematopoietic stem cells.
Figure 2: The HSC response to M. avium infection is dependent upon intact IFN-γ signalling.
Figure 3: IFN-γ is sufficient to induce HSC proliferation in vitro.
Figure 4: IFN-γ is sufficient to induce HSC proliferation in vivo.
Figure 5: Basal IFN-γ tone affects HSC cycling and function.

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Acknowledgements

We thank C. Feng and A. Sher for providing Mycobacterium avium. We also thank D. Levy and C. Schindler for providing us with Stat1 and Ifnar1 knockout mice. We are grateful to G. Challen for providing information about Ifngr1, to Y. Zheng and S. Wu for technical assistance, and to J. Gilbert for critical reading of the manuscript. M.T.B. is supported by the NIDDK institute of the National Institutes of Health (NIH), and K.Y.K. was supported by the Adeline B. Landa Fellowship of the Texas Children’s Hospital Auxiliary and the Simmons Foundation Collaborative Research Fund. This work was supported by the NIDDK, NHLBI, NCI and NIBIB institutes of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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M.T.B. and K.Y.K. designed experiments, performed flow cytometry, transplants, and quantitative real-time PCR analysis, and analysed data. K.Y.K. performed immunohistochemistry. N.C.B. performed flow cytometry and cytokine analysis. D.C.W. assisted with study design. M.T.B., K.Y.K. and M.A.G. wrote the manuscript. All authors discussed results and commented on the manuscript.

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Correspondence to Margaret A. Goodell.

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Baldridge, M., King, K., Boles, N. et al. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010). https://doi.org/10.1038/nature09135

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