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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Kox, Matthijs¹  Kleijn, Stan²  Jonge, Marien I.³  Gerretsen, Jelle⁴  Pickkers, Peter⁵ 

[1] and;and..Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;..Radboud Center for Infectious Diseases (RCI), Nijmegen, The Netherlands;Laboratory of Pediatric Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands;Radboud Center for Infectious Diseases (RCI), Nijmegen, The Netherlands

关键词: sepsis;    granulocytes;    immune suppression;    cytokine;    splenectomy;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY