title: IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ.
abstract: African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survival. Here we demonstrate that infection with African trypanosomes of IL-27 receptor-deficient (IL-27R-/-) mice results in severe liver immunopathology and dramatically reduced survival as compared to wild-type mice. This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ. What is important is that IL-10 production was not impaired in infected IL-27R-/- mice. Depletion of CD4+ T cells in infected IL-27R-/- mice resulted in a dramatically reduced production of IFN-γ, preventing the early mortality of infected IL-27R-/- mice. This was accompanied by a significantly reduced inflammatory response and a major amelioration of liver pathology. These results could be mimicked by treating IL-27R-/- mice with a neutralizing anti-IFN-γ antibody. Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes. These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Gongguan
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Donglei
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Animal Genetics, Breeding and Reproduction, South China Agricultural University, Guangzhou, China.
authors.forename: Xiquan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory for Cellular and Molecular Immunology, Vrije Universiteit Brussels, Brussels, Belgium; Structural Biology Research Centre, VIB, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Magez
authors.affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Meiqing
authors.initials: M
authors.lastname: Shi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D007371:Interferon-gamma / Q000096:biosynthesis*; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014345:Trypanosoma / Q000276:immunology; D014352:Trypanosomiasis / Q000276:immunology*
chemical_list: C486767:Il27 protein, mouse; D007378:Interleukins; D007371:Interferon-gamma