IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ.

TitleIL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ.
Publication TypeJournal Article
Year of Publication2015
AuthorsLiu, G., J. Xu, H. Wu, D. Sun, X. Zhang, X. Zhu, S. Magez, and M. Shi
JournalPLoS Pathog
Volume11
Issue7
Paginatione1005065
Date Published2015 Jul
ISSN1553-7374
KeywordsAnimals, CD4-Positive T-Lymphocytes, Cell Death, Interferon-gamma, Interleukins, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Trypanosoma, Trypanosomiasis
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.

DOI10.1371/journal.ppat.1005065
Alternate JournalPLoS Pathog.
PubMed ID26222157
PubMed Central IDPMC4519326
Research group: