期刊
MBIO
卷 12, 期 1, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/mBio.03385-20
关键词
parasites; African trypanosomes; IL-27; Tip-DCs; Ly6C(+) monocytes; Ly6C(-) monocytes; IFN-gamma; intravital imaging; murine model of African trypanosomiasis; liver immunity; host-pathogen interactions
类别
资金
- U.S. Fulbright Program
- Chinese Scholarship Council (CSC)
- University of Maryland
Tip-DCs are key immune effector cells involved in fighting off various infections, but their excessive development can lead to tissue damage. This study reveals that IL-27 plays a crucial role in inhibiting Tip-DC development during parasitic infections by interfering with the CD4(+) T cell-IFN-gamma axis and preserving the balance between Ly6C(-) and Ly6C(+) monocytes. Targeting IL-27 signaling may offer a promising approach for therapeutic intervention to control Tip-DC development.
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 (Ly6C(+)) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R(-/-) mice. Mechanistically, Ly6C(+) monocyte differentiation into pathogenic Tip-DCs in infected IL- 27R(-/-) mice is driven by a CD4(+) T cell-interferon gamma (IFN-gamma) axis via cell-intrinsic IFN-gamma signaling. In parallel, hyperactive IFN-gamma signaling induces cell death of Ly6C-negative (Ly6C(-)) 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 Ly6C(-) monocytes on Ly6C(+) monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD4(+) T cell-IFN-gamma axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-gamma and that the regulation involves CD4(+) T cells and Ly6C(-) monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention. IMPORTANCE TNF/iNOS-producing dendritic cells (Tip-DCs) are at the front line as immune effector cells to fight off a broad range of invading microbes. Excessive development of Tip-DCs contributes to tissue destruction. Thus, identifying master regulators of Tip-DC development is fundamental for developing new therapeutic strategies. Here, we identify Tip-DCs as a terminal target of IL-27, which prevents Tip-DC-mediated early mortality during parasitic infections. We demonstrate that IL-27 inhibits Tip-DC development via a dual-track mechanism involving the complex interactions of effector CD4(+) T cells, Ly6C(-) monocytes, and Ly6C(+) monocytes. These findings delineate an in-depth view of mechanisms of Tip-DC differentiation that may have significant implications for the ongoing development of IL-27-based immunotherapy.
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