Cutting Edge: Developmental Regulation of IFN-γ Production by Mouse Neutrophil Precursor Cells

Sturge, Carolyn R.; Burger, Elise; Raetz, Megan; Hooper, Lora V.; Yarovinsky, Felix

doi:10.4049/jimmunol.1500366

Cited by 14 publications

(11 citation statements)

References 28 publications

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“…These results corroborate earlier findings of a splenic subpopulation of neutrophils that produce significant amounts of IFN-g after Listeria monocytogenes infection in mice [24]. Notably, no increased de novo IFN-g expression by murine neutrophils obtained from peritoneal cavity, peripheral blood, and bone marrow was demonstrated after infection with Toxoplasma gondii [25]. These observations suggest that neutrophilic IFN-g production is stimulus/infection-and/or site specific.…”

Section: Discussionsupporting

confidence: 91%

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

Langereis

Pickkers

Kleijn

et al. 2017

Journal of Leukocyte Biology

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The immune inhibitory checkpoint molecule programmed death ligand (PD-L)-1 is increasingly recognized as an important player in the immune suppression observed in patients with sepsis, but its role has mainly been studied in monocytes. In an earlier study, we demonstrated that experimental human endotoxemia results in mobilization of a subset of PD-L1-expressing neutrophils displaying an IFN-γ-induced transcriptome profile. Herein, we identify the source of IFN-γ production during murine endotoxemia and its role in the generation of PD-L1-suppressive neutrophils. We demonstrate that, similar to what we found in humans, murine endotoxemia results in the influx of a subset of PD-L1 neutrophils in the circulation, and incubation of mouse neutrophils with recombinant IFN-γ profoundly increases PD-L1 expression. Furthermore, administration of anti-IFN-γ abrogated the generation of PD-L1 neutrophils in endotoxemic mice. The critical involvement of the spleen is illustrated by the fact that splenectomy nullified circulating IFN-γ levels and substantially reduced the abundance of PD-L1 neutrophils, whereas cotreatment with recombinant IFN-γ resulted in complete restoration of generation of PD-L1 neutrophils in splenectomized mice. Finally, the functional importance of spleen-derived PD-L1 neutrophils is exemplified by the finding that the profound decrease in T-lymphocyte proliferation observed in cells from endotoxemic mice was attenuated in cells from splenectomized animals. We demonstrated that spleen-derived IFN-γ induces generation of PD-L1-suppressive neutrophils, implying that the spleen is critically involved in immune suppression during inflammatory diseases such as sepsis. Furthermore, our data suggest that IFN-γ plays a dual role by enhancing innate immunity and at the same time suppressing adaptive immune responses.

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Section: Discussionsupporting

confidence: 91%

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

Langereis

Pickkers

Kleijn

et al. 2017

Journal of Leukocyte Biology

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“…This cluster was not identified in earlier hematopoiesis studies as the neutrophil marker Ly6G was routinely excluded from flow cytometry panels at that time. ScRNA-Seq analysis of this Ly6G-containing Cluster#C further revealed 2 populations: an early-stage progenitor (#C1) with stem-cell morphology and little Ly6G expression and a late-stage precursor (#C2) that expressed low levels of Ly6G with morphological features similar to transient neutrophil precursors (Figure 2D and S3B) (Evrard et al, 2018; Satake et al, 2012; Sturge et al, 2015; Yáñez et al, 2015). Recently, a late-stage neutrophil precursor was identified in bone marrow of mice (Kim et al, 2017).…”

Section: Discussionmentioning

confidence: 94%

“…Siglec F (cluster#A) marks eosinophils, CD115 (cluster#B) marks monocytes, Ly6G (cluster#C) marks neutrophils, FcεRIα (cluster#D) marks mast cells and basophils, and CD16/32 and CD34 (cluster#E) marks both CMP and GMP. The neutrophil-specific antigen, Ly6G, is observed in a continuum from negative to high expression in Cluster#C, suggesting the presence of neutrophil progenitors and precursors within this cluster (Kim et al, 2017; Satake et al, 2012; Sturge et al, 2015; Yáñez et al, 2015). We confirmed these results using conventional flow cytometry (Figure S2A, B).…”

Section: Resultsmentioning

confidence: 99%

“…Several immature neutrophil precursors have also been identified (Fiedler and Brunner, 2012; Kim et al, 2017; Satake et al, 2012; Sturge et al, 2015; Yáñez et al, 2015). However, these precursors are late-stage precursors with neutrophil potency (Kim et al, 2017; Sturge et al, 2015), and several show multi- or oligopotency (Satake et al, 2012; Yáñez et al, 2015). Recently, a proliferative neutrophil precursor was identified in mouse BM that generates neutrophils after intra-BM adoptive transfer (Evrard et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Identification of an Early Unipotent Neutrophil Progenitor with Pro-tumoral Activity in Mouse and Human Bone Marrow

et al. 2018

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Neutrophils are short-lived cells that play important roles in both health and disease. Neutrophils and monocytes originate from the granulocyte monocyte progenitor (GMP) in bone marrow; however, unipotent neutrophil progenitors are not well defined. Here, we use cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) methodologies to identify a committed unipotent early-stage neutrophil progenitor (NeP) in adult mouse bone marrow. Importantly, we found a similar unipotent NeP (hNeP) in human bone marrow. Both NeP and hNeP generate only neutrophils. NeP and hNeP both significantly increase tumor growth when transferred into murine cancer models, including a humanized mouse model. hNeP are present in the blood of treatment-naive melanoma patients but not of healthy subjects. hNeP can be readily identified by flow cytometry and could be used as a biomarker for early cancer discovery. Understanding the biology of hNeP should allow the development of new therapeutic targets for neutrophil-related diseases, including cancer.

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“…Research has shown that IFN-γ plays a crucial role in host resistance to numerous intracellular pathogens, including Salmonella, Mycobacterium tuberculosis , Leishmania major and Toxoplasma gondii 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Although much of the attention has been focused on T cell-derived IFN-γ in determining host resistance to pathogens, recent reports have shown a contribution of NK cells, group 1 innate lymphoid cells (ILC1s), and neutrophils in mediating type I immunity against intracellular pathogens 11 , 12 , 13 , 14 , 15 , 16 , 17 . Failure to produce IFN-γ in a time and cell-type specific manner results in acute susceptibility to all groups of intracellular pathogens, including viruses, bacteria, and protozoan parasites 18 , 19 , 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection

López-Yglesias¹,

Burger²,

Araujo³

et al. 2018

Mucosal Immunology

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Coordinated production of IFN-γ by innate and adaptive immune cells is central for host defense, but can also trigger immunopathology. The investigation of the lymphoid cell-specific contribution to the IFN-γ-mediated intestinal pathology during Toxoplasma gondii infection identified CD4+ T cells as a key cell population responsible for IFN-γ-dependent intestinal inflammation and Paneth cell loss, where T-bet-dependent ILC1 cells play a minor role in driving the parasite-induced immunopathology. This was evident from the analysis of T-bet deficiency that did not prevent the intestinal inflammation and instead revealed that T-bet-deficient CD4+ Th1 cells are sufficient for T. gondii-triggered acute ileitis and Paneth cell loss. These results revealed that T-bet independent Th1 effector cells are major functional mediators of the type I immunopathological response during acute gastrointestinal infection.

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Cutting Edge: Developmental Regulation of IFN-γ Production by Mouse Neutrophil Precursor Cells

Cited by 14 publications

References 28 publications

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

Identification of an Early Unipotent Neutrophil Progenitor with Pro-tumoral Activity in Mouse and Human Bone Marrow

T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection

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