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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

Depletion of CD4+, but not CD8+, T cells significantly reduces the production of inflammatory cytokines and the serum activities of ALT, and enhances the survival of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.IL-27R-/- mice were infected with T. congolense, and treated with 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. (A) Parasitemia and survival of the IL-27R-/- mice (n = 4–5) infected with T. congolense. (B) Serum ALT activities were assessed in IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. (C) Plasma levels of IFN-γ, IL-12p40, and TNF-α of IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2 separate experiments.
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ppat.1005065.g006: Depletion of CD4+, but not CD8+, T cells significantly reduces the production of inflammatory cytokines and the serum activities of ALT, and enhances the survival of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.IL-27R-/- mice were infected with T. congolense, and treated with 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. (A) Parasitemia and survival of the IL-27R-/- mice (n = 4–5) infected with T. congolense. (B) Serum ALT activities were assessed in IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. (C) Plasma levels of IFN-γ, IL-12p40, and TNF-α of IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2 separate experiments.

Mentions: As shown above, CD4+ T cells were excessively activated in the liver of IL-27R-/- mice infected with African trypanosomes, raising the possibility that the early mortality of infected IL-27R-/- mice was a consequence of a CD4+ T cell-dependent immune-mediated pathology. To test this, IL-27R-/- mice infected with T. congolense were treated with depleting anti-mouse CD4 mAb, anti-mouse CD8 mAb, or rat IgG as control; and the course of infection, immune responses, and severity of liver damage were assessed. As shown in S1 Fig, administration of the antibodies efficiently depleted CD4+ T cells or CD8+ T cells in the spleen and liver of the infected mice. Infected mice from all three groups could effectively control the first wave of parasitemia, although depletion of CD4+ T cells resulted in a significantly higher parasitemia at some time points of infection (p<0.01 or <0.05, Fig 6A). Strikingly, infected IL-27R-/- mice treated with anti-CD4 mAb had two fold increase of survival compared to infected IL-27R-/- mice treated with rat IgG (p<0.01, Fig 6A). In contrast, depletion of CD8+ T cells did not affect the survival of infected IL-27R-/- mice (Fig 6A). These results demonstrated that IL-27 signaling had a crucial role in dampening CD4+ T cell activation in experimental T. congolense infection in mice, allowing for prolonged survival.


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)

Depletion of CD4+, but not CD8+, T cells significantly reduces the production of inflammatory cytokines and the serum activities of ALT, and enhances the survival of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.IL-27R-/- mice were infected with T. congolense, and treated with 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. (A) Parasitemia and survival of the IL-27R-/- mice (n = 4–5) infected with T. congolense. (B) Serum ALT activities were assessed in IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. (C) Plasma levels of IFN-γ, IL-12p40, and TNF-α of IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2 separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4519326&req=5

ppat.1005065.g006: Depletion of CD4+, but not CD8+, T cells significantly reduces the production of inflammatory cytokines and the serum activities of ALT, and enhances the survival of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.IL-27R-/- mice were infected with T. congolense, and treated with 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. (A) Parasitemia and survival of the IL-27R-/- mice (n = 4–5) infected with T. congolense. (B) Serum ALT activities were assessed in IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. (C) Plasma levels of IFN-γ, IL-12p40, and TNF-α of IL-27R-/- mice (n = 4) on day 7 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2 separate experiments.
Mentions: As shown above, CD4+ T cells were excessively activated in the liver of IL-27R-/- mice infected with African trypanosomes, raising the possibility that the early mortality of infected IL-27R-/- mice was a consequence of a CD4+ T cell-dependent immune-mediated pathology. To test this, IL-27R-/- mice infected with T. congolense were treated with depleting anti-mouse CD4 mAb, anti-mouse CD8 mAb, or rat IgG as control; and the course of infection, immune responses, and severity of liver damage were assessed. As shown in S1 Fig, administration of the antibodies efficiently depleted CD4+ T cells or CD8+ T cells in the spleen and liver of the infected mice. Infected mice from all three groups could effectively control the first wave of parasitemia, although depletion of CD4+ T cells resulted in a significantly higher parasitemia at some time points of infection (p<0.01 or <0.05, Fig 6A). Strikingly, infected IL-27R-/- mice treated with anti-CD4 mAb had two fold increase of survival compared to infected IL-27R-/- mice treated with rat IgG (p<0.01, Fig 6A). In contrast, depletion of CD8+ T cells did not affect the survival of infected IL-27R-/- mice (Fig 6A). These results demonstrated that IL-27 signaling had a crucial role in dampening CD4+ T cell activation in experimental T. congolense infection in mice, allowing for prolonged survival.

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