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

Abstract

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.

The endotoxin-induced pulmonary inflammatory response is enhanced during the acute phase of influenza infection

“…To determine the number of animals required per group, we performed a power calculation based on a minimal detectable difference of 50% in LPS-induced plasma TNF-α levels between influenza-infected and non-influenza-infected mice. Mean ± SD (533 ± 163 pg/mL) TNF-α plasma levels were obtained from previous work from our group, in which male C57BL/6J mice were also injected intravenously with 5 mg/kg LPS and sacrificed 90 min later [ 14 ]. Using a two-sided α of 0.05 and a power of 80% (β of 0.2) in an unpaired t test design, six animals per group were required.…”

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…The phenotypic and functional features of these suppressive neutrophil populations have been extensively reviewed elsewhere . Murine PMN‐MDSCs have been shown to suppress T‐cell function mostly through ROS production or, as shown more recently, via PD‐L1 expression, or S100A9‐mediated up‐regulation of prostaglandin E 2 . Similar to human suppressive neutrophils, our knowledge on the specific features of murine PMN‐MDSCs is limited by the lack of specific markers that distinguish them from normal neutrophils.…”

The Dual Nature of Type I and Type II Interferons

“…In conjunction with GM-CSF, IFN-γ was shown to differentiate monocytes into myeloid derived suppressor cells (MDSCs) in vitro ( 92 ). In a mouse model of endotoxemia, IFN-γ has also been shown to upregulate PD-L1 on neutrophils ( 93 ). A table comparing the effects of IFN-γ on the innate immune response is summarized in Table 2 .…”