TY - JOUR
T1 - Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection
AU - Baldridge, Megan T.
AU - King, Katherine Y.
AU - Boles, Nathan C.
AU - Weksberg, David C.
AU - Goodell, Margaret A.
N1 - Funding Information:
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.
PY - 2010/6/10
Y1 - 2010/6/10
N2 - Lymphocytes and neutrophils are rapidly depleted by systemic infection. 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 unknown. 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 tuberculosis.
AB - Lymphocytes and neutrophils are rapidly depleted by systemic infection. 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 unknown. 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 tuberculosis.
UR - http://www.scopus.com/inward/record.url?scp=77953462161&partnerID=8YFLogxK
U2 - 10.1038/nature09135
DO - 10.1038/nature09135
M3 - Article
C2 - 20535209
AN - SCOPUS:77953462161
VL - 465
SP - 793
EP - 797
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7299
ER -