IL-27 Negatively Regulates Tip-DC Development during Infection

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Publication or External Link
https://doi.org/10.1128/mBio.03385-20
Date
2021-02-16
Authors
Liu, Gongguan
Abas, Osama
Fu, Yong
Chen, Yanli
Strickland, Ashley B.
Sun, Donglei
Shi, Meiqing
Advisor
Citation
Liu G, Abas O, Fu Y, Chen Y, Strickland AB, Sun D, Shi M. 2021. IL-27 negatively regulates Tip-DC development during infection. mBio 12:e03385-20.
DRUM DOI
https://doi.org/10.13016/rrni-rchr
Abstract
Tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (Tip-DCs) have profound impacts on host immune responses during infections. The mechanisms regulating Tip-DC development remain largely unknown. Here, using a mouse model of infection with African trypanosomes, we show that a deficiency in interleukin-27 receptor (IL-27R) signaling results in escalated intrahepatic accumulation of Ly6C-positive (Ly6C1) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R2/2 mice. Mechanistically, Ly6C1 monocyte differentiation into pathogenic Tip-DCs in infected IL-27R2/2 mice is driven by a CD41 T cell-interferon gamma (IFN-g) axis via cell-intrinsic IFN-g signaling. In parallel, hyperactive IFN-g signaling induces cell death of Ly6C-negative (Ly6C2) monocytes in a cell-intrinsic manner, which in turn aggravates the development of pathogenic Tip-DCs due to the loss of the negative regulation of Ly6C2 monocytes on Ly6C1 monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD41 T cell–IFN-g axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-g and that the regulation involves CD41 T cells and Ly6C2 monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention.
Notes
Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.
URI (handle)
http://hdl.handle.net/1903/28660
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Department of Veterinary Medicine Research Works