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

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-gamma. 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-gamma, 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-gamma 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-gamma 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.