Quiescent hematopoietic stem cells are activated by IFNγ in response to chronic infection

By Megan T. Baldridge, K. King, Nathan C. Boles, D. Weksberg, Margaret A. Goodell. Nature, 2010

877 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/6d28660db6efe9e9a14e519f3b91df0dc84d7840

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In Immunology

1. Ryan M. O’Connell
2. D. Rao
3. David Baltimore
4. Christoph Bock

In Oncology

1. Jean-Pierre Issa
2. Grant A. Challen
3. J. Slingerland

Citations in the corpus

• microRNA regulation of inflammatory responses. (2012, background): “Recent studies have demonstrated that HSCs respond to IFN signaling by proliferating and that this constitutes an important response to infection (88).”
• Dnmt3a is essential for hematopoietic stem cell differentiation (2011, methodology): “Control mice throughout this study (unless otherwise specified) consisted of Dnmt3a fl / fl littermates lacking Mx1 - Cre , which were treated identically to experimental mice, including receiving injections of pIpC to control for interferon-mediated effect”
• Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion (2018, background): “For instance, constitutive expression of endogenous IFN-γ contributes to the homeostasis of immune cell functions (57), maintenance of the hematopoietic stem cell niche (58), and bone formation (59).”
• Arteriolar niches maintain haematopoietic stem cell quiescence (2013, neutral): “While most HSCs are quiescent under homeostasis 9 , they can undergo activation for example by interferon-mediated signals 7,10,11 .”
• Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. (2014, background): “Both antiviral and NOTCH signaling have roles in controlling normal and cancer stem cells (Baldridge et al., 2010; Ranganathan et al., 2011).”