Editors' ChoiceImmunology

More Myeloid Cells, STAT!

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Science Signaling  15 Apr 2014:
Vol. 7, Issue 321, pp. ec98
DOI: 10.1126/scisignal.2005370

Whereas lymphocytes (T cells and B cells) are relatively long-lived and can proliferate in response to infection or tissue damage, myeloid cells, such as granulocytes and macrophages, are short-lived and must be replenished by proliferation and differentiation from hematopoietic stem cells (HSCs) (see Welner and Kincade). Zhao et al. and Schürch et al. identified mechanisms by which hematopoietic stem and progenitor cells (HSPCs) instruct the rapid mobilization of myeloid cells in response to models of infection. Zhao et al. performed high-throughput, single-cell cytokine secretion analysis of HSPCs [LinSca1+cKit+ (LSK) cells, which represent a mixed population of HSPCs]. In response to exposure to ligands that activated Toll-like receptor 2 and 4 (TLR2 and TLR4), these cells produced large amounts of many different cytokines; interleukin-6 (IL-6) was the most abundantly produced. On the basis of their cytokine production profiles, the cells were classified into four groups: those secreting the least amount of cytokines; those with a secreted cytokine profile associated with myeloid production; those with a secreted cytokine profile associated with lymphocyte production; and those that secreted all of the tested cytokines. LSK cells isolated from a mouse with a RELA-green fluorescent protein (GFP) fusion (RELA encodes a subunit of the transcription factor NF-κB) exhibited NF-κB activity in response to the TLR2 and TLR4 ligands. The importance of NF-κB signaling for the TLR-dependent stimulation of cytokine production was demonstrated with cells from mice lacking either a subunit of NF-κB (p50 KO), in which cytokine production was reduced, or a negative regulator (miR-146a KO) of the pathway, in which cytokine production was enhanced. Furthermore, conditioned medium from bone marrow cells exposed to the TLR2 and TLR4 ligands stimulated myeloid differentiation more effectively than did conditioned medium from bone marrow depleted of LSK cells, and the medium collected from miR-146a KO LSK cells showed the greatest induction of myeloid differentiation. Unexpectedly, LSK cells produced more cytokines, both in the types and quantity, than were produced by mature myeloid or lymphoid cells, which suggests that infection, which would trigger TLR signaling, could result in a large stem cell niche–specific increase in cytokine production. Injection of HSPCs from wild-type mice, the miR-146a KO mice, or IL-6 KO mice into mice that had been irradiated to produce leucopenia showed that delivery of a TLR4 ligand–stimulated myelopoeisis through a pathway involving NF-κB signaling and IL-6 production from the HSPCs. Thus, HSPCs are not only the source of myeloid progenitors, but also respond to danger signals to produce the cytokine signals for their own differentiation.

In a related study, Schürch et al. investigated the role of cytotoxic T lymphocytes (CTLs) in stimulating myeloid cell production using various combinations of engineered and mutant mice. Injection of CTLs engineered to respond to a specific viral antigen (p14 CTLs) expressed by the host mice (H8 mice) resulted in a decrease in the total number of cells in the bone marrow of the host mice, but an increase in the number of HSPCs that could be isolated from the bone marrow. These isolated HSPCs exhibited an increased ability to form myeloid cells in culture and, when isolated 2 days after p14 CTL exposure and transferred into a new host mouse, these cells produced an increase in myeloid cells in the host mouse blood, which indicated an increase in myeloid lineage–primed progenitors. Induction of myeloid differentiation required interferon-γ (IFN-γ), because the response was lost if the p14 CTLs were IFN-γ–deficient or if the H8 host mice were deficient in the IFN-γ receptor. Analysis of several types of mice engineered with hematopoietic cells, including HSPCs, and bone marrow niche cells with different genetic deficiencies revealed that the HSPCs did not respond directly to IFN-γ, but that other cells in the niche were responding. Implantation of artificial bone marrow populated with stromal cells from wild-type mice or IFN-γ receptor–deficient mice, followed by injection of p14 CTLs, showed that the IFN-γ–responsive stromal cells were responsible for stimulating myeloid cell production. Of the cells in the bone marrow HSC niche, only mesenchymal stromal cells were positive for the IFN-γ receptor. Bone marrow stromal cell lines produced IL-6 in response to IFN-γ, and blocking IL-6 activity prevented these cells from stimulating myeloid cell differentiation in coculture experiments. Experiments with mice with IL-6–deficient niche cells confirmed the importance of IL-6 in mediating myeloid cell production and viral clearance in vivo. Thus, IFN-γ released from T cells in response to infection stimulates the mesenchymal stromal cells of the bone marrow HSC niche to produce IL-6, which promotes the production of myeloid cells to combat the infection. Together, these two studies reveal unexpected cytokine-signaling roles for stromal cells and HSPCs themselves in the acute myeloid cell response to infection.

J. L. Zhao, C. Ma, R. M. O’Connell, A. Mehta, R. DiLoreto, J. R. Heath, D. Baltimore, Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14, 445–459 (2014). [PubMed]

C. M. Schürch, C. Riether, A. F. Ochsenbein, Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells. Cell Stem Cell 14, 460–472 (2014). [PubMed]

R. S. Welner, P. W. Kincade, 9-1-1: HSCs respond to emergency calls. Cell Stem Cell 14, 415–416 (2014). [PubMed]

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