Key Points: Antibiotics cause multilineage alterations in murine hematopoiesis, with marked suppression of multipotent progenitors. Suppression of bone marrow populations results from depletion of intestinal microbiota.

Chronic infections affect a third of the world's population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4-6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFN-γ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFN-γ, transcriptome analysis pointed toward increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFN-γ-induced HSPC differentiation. Gain- and loss-of-function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation.

Interferon gamma (IFNγ) promotes cell division of hematopoietic stem cells (HSCs) without affecting the total HSC number. We postulated that IFNγ stimulates differentiation of HSCs as part of the innate immune response. Here, we report that type II interferon signaling is required, both at baseline and during an animal model of LCMV infection, to maintain normal myeloid development. By separately evaluating myeloid-biased and lymphoid-biased HSC subtypes, we found that myeloid-biased HSCs express higher levels of IFNγ receptor and are specifically activated to divide after recombinant IFNγ exposure in vivo. While both HSC subtypes show increased expression of the transcription factor C/EBPβ after infection, only the myeloid-biased HSCs are transiently depleted from the marrow during the type II interferon-mediated immune response to Mycobacterium avium infection, as measured both functionally and phenotypically. These findings indicate that IFNγ selectively permits differentiation of myeloid-biased HSCs during an innate immune response to infection. This represents the first report of a context and a mechanism for discriminate utilization of the alternate HSC subtypes. Terminal differentiation, at the expense of self-renewal, may compromise HSC populations during states of chronic inflammation. Stem Cells 2014;32:3023–3030

Purpose of Review Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that participates in the regulation of hematopoietic stem cells (HSC) during development and under homeostatic conditions. IFN-γ also plays a key pathogenic role in several diseases that affect hematopoiesis including aplastic anemia, hemophagocytic lymphohistiocytosis, and cirrhosis of the liver. Recent Findings Studies have shown that increased IFN-γ negatively affects HSC homeostasis, skewing HSC towards differentiation over self-renewal and eventually causing exhaustion of the HSC compartment. Summary Here, we explore the mechanisms by which IFN-γ regulates HSC in both normal and pathological conditions. We focus on the role of IFN-γ signaling in HSC fate decisions, and the transcriptional changes it elicits. Elucidating the mechanisms through which IFN-γ regulates HSCs may lead to new therapeutic options to prevent or treat adverse hematologic effects of the many diseases to which IFN-γ contributes.