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

Liu G, Xu J, Wu H, Sun D, Zhang X, Zhu X, Magez S, Shi M - PLoS Pathog. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

IL-27 signaling plays a crucial role in dampening Th1 mediated immune responses, allowing prolonged survival of mice infected with T. brucei.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. brucei on day 6 and 9 versus day 0 (uninfected). (B) Parasitemia and survival of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–7) infected with T. brucei. (C) Production of IFN-γ detected on day 6 in the plasma and supernatant fluids of cultured spleen cells and serum activities of ALT examined on day 6 and 9 in IL-27R-/- and wild-type mice after infection with T. brucei. (D) Survival of IL-27R-/- mice (n = 5–6) infected with T. brucei, following administration of 0.5 mg rat anti-mouse CD4 mAb, rat anti-mouse CD8 mAb, or rat IgG on day 0, 2, 4, and 6 after infection, respectively. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
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ppat.1005065.g008: IL-27 signaling plays a crucial role in dampening Th1 mediated immune responses, allowing prolonged survival of mice infected with T. brucei.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. brucei on day 6 and 9 versus day 0 (uninfected). (B) Parasitemia and survival of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–7) infected with T. brucei. (C) Production of IFN-γ detected on day 6 in the plasma and supernatant fluids of cultured spleen cells and serum activities of ALT examined on day 6 and 9 in IL-27R-/- and wild-type mice after infection with T. brucei. (D) Survival of IL-27R-/- mice (n = 5–6) infected with T. brucei, following administration of 0.5 mg rat anti-mouse CD4 mAb, rat anti-mouse CD8 mAb, or rat IgG on day 0, 2, 4, and 6 after infection, respectively. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.

Mentions: We finally characterized the role of IL-27 signaling in regulation of immune responses during T. brucei infection. In contrast to T. congolense, T. brucei species have the ability to penetrate the walls of capillaries, invade interstitial tissues, including the brain tissues, thus serving as a model of human African trypanosomiasis [48,49]. T. brucei infection also upregulated the mRNA expressions of IL-27p28 and EBI3, but not IL-27R-/- in the liver of mice (Fig 8A). IL-27R-/- mice infected with T. brucei efficiently controlled the first wave of parasitemia as infected wild-type did, but survived significantly shorter than infected wild-type mice (15 days vs. 32 days, p<0.01, Fig 8B), demonstrating an essential role of IL-27 signaling in prevention of the early mortality of mice infected with T. brucei. IL-27R-/- mice infected with T. brucei also showed enhanced IFN-γ production in plasma and supernatant fluids of spleen cultures, as well as enhanced serum activities of ALT, compared to infected wild-type mice (p<0.01 or <0.05, Fig 8C). Importantly, depletion of CD4+, but not CD8+, T cells enhanced the survival of IL-27R-/- mice infected with T. brucei by 3 folds (p<0.01, Fig 8D). Thus, IL-27 signaling is also required for survival of mice via preventing excessive Th1 immune responses during T. brucei infection.


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

Liu G, Xu J, Wu H, Sun D, Zhang X, Zhu X, Magez S, Shi M - PLoS Pathog. (2015)

IL-27 signaling plays a crucial role in dampening Th1 mediated immune responses, allowing prolonged survival of mice infected with T. brucei.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. brucei on day 6 and 9 versus day 0 (uninfected). (B) Parasitemia and survival of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–7) infected with T. brucei. (C) Production of IFN-γ detected on day 6 in the plasma and supernatant fluids of cultured spleen cells and serum activities of ALT examined on day 6 and 9 in IL-27R-/- and wild-type mice after infection with T. brucei. (D) Survival of IL-27R-/- mice (n = 5–6) infected with T. brucei, following administration of 0.5 mg rat anti-mouse CD4 mAb, rat anti-mouse CD8 mAb, or rat IgG on day 0, 2, 4, and 6 after infection, respectively. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4519326&req=5

ppat.1005065.g008: IL-27 signaling plays a crucial role in dampening Th1 mediated immune responses, allowing prolonged survival of mice infected with T. brucei.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. brucei on day 6 and 9 versus day 0 (uninfected). (B) Parasitemia and survival of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–7) infected with T. brucei. (C) Production of IFN-γ detected on day 6 in the plasma and supernatant fluids of cultured spleen cells and serum activities of ALT examined on day 6 and 9 in IL-27R-/- and wild-type mice after infection with T. brucei. (D) Survival of IL-27R-/- mice (n = 5–6) infected with T. brucei, following administration of 0.5 mg rat anti-mouse CD4 mAb, rat anti-mouse CD8 mAb, or rat IgG on day 0, 2, 4, and 6 after infection, respectively. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
Mentions: We finally characterized the role of IL-27 signaling in regulation of immune responses during T. brucei infection. In contrast to T. congolense, T. brucei species have the ability to penetrate the walls of capillaries, invade interstitial tissues, including the brain tissues, thus serving as a model of human African trypanosomiasis [48,49]. T. brucei infection also upregulated the mRNA expressions of IL-27p28 and EBI3, but not IL-27R-/- in the liver of mice (Fig 8A). IL-27R-/- mice infected with T. brucei efficiently controlled the first wave of parasitemia as infected wild-type did, but survived significantly shorter than infected wild-type mice (15 days vs. 32 days, p<0.01, Fig 8B), demonstrating an essential role of IL-27 signaling in prevention of the early mortality of mice infected with T. brucei. IL-27R-/- mice infected with T. brucei also showed enhanced IFN-γ production in plasma and supernatant fluids of spleen cultures, as well as enhanced serum activities of ALT, compared to infected wild-type mice (p<0.01 or <0.05, Fig 8C). Importantly, depletion of CD4+, but not CD8+, T cells enhanced the survival of IL-27R-/- mice infected with T. brucei by 3 folds (p<0.01, Fig 8D). Thus, IL-27 signaling is also required for survival of mice via preventing excessive Th1 immune responses during T. brucei infection.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus