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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

Enhanced activation of CD4+ T cells and elevated production of inflammatory cytokines in the liver of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) The frequency (left and upper right) and the absolute number (lower right) of activated CD4+ T cells (CD44hiCD62Llow) derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0 and 7 after infection with T. congolense. (B) Production of IFN-γ, IL-12p40, and TNF-α in the supernatant fluids of cultured liver leukocytes purified from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. (C) The frequency (left and upper right) and the absolute number (lower right) of IFN-γ-producing CD4+ T cells derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0, 7 and 10 after infection with T. congolense following 12 h in vitro restimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
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ppat.1005065.g005: Enhanced activation of CD4+ T cells and elevated production of inflammatory cytokines in the liver of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) The frequency (left and upper right) and the absolute number (lower right) of activated CD4+ T cells (CD44hiCD62Llow) derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0 and 7 after infection with T. congolense. (B) Production of IFN-γ, IL-12p40, and TNF-α in the supernatant fluids of cultured liver leukocytes purified from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. (C) The frequency (left and upper right) and the absolute number (lower right) of IFN-γ-producing CD4+ T cells derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0, 7 and 10 after infection with T. congolense following 12 h in vitro restimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.

Mentions: Because early mortality of IL-27R-/- mice infected with African trypanosomes was associated with severe liver pathology without impaired secretion of IL-10 as shown above and because IL-27 has been shown to mainly regulate T cell, particularly CD4+ T cell activation during infection with intracellular pathogens [38–42], we next characterized CD4+ T cell responses in the liver of IL-27R-/- mice during infection with T. congolense. We found that the frequency and the absolute number of activated hepatic CD4+ T cells (CD44hiCD62Llow) were significantly higher in IL-27R-/- mice infected with T. congolense, compared to infected wild-type mice (p<0.01, Fig 5A). The production of IFN-γ, IL-12p40, and TNF-α by cultured liver leukocytes from infected IL-27R-/- mice was significantly higher than production of these cytokines by liver leukocytes from infected wild-type mice (p<0.001, <0.01 or <0.05, Fig 5B). In particular, the production of IFN-γ was enhanced by 4–8 folds in the liver leukocyte cultures of infected IL-27R-/- mice (Fig 5B). Thus, we further evaluated the activation of liver CD4+ T cells by examining their secretions of IFN-γ using single cell analysis. A small and similar percentage and absolute number of CD4+ T cells from uninfected wild-type and IL-27R-/- mice secreted IFN-γ after 12 h stimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). In contrast, by day 7 and 10 post infection significantly higher percentage and absolute number of IFN-γ-producing CD4+ T cells were detected in IL-27R-/- mice as compared to wild-type cohorts (Fig 5C). Collectively, these data suggested that the early mortality of IL-27R-/- mice infected with African trypanosomes was associated with exacerbated Th1-mediated immune responses with overactivation of CD4+ T cells.


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)

Enhanced activation of CD4+ T cells and elevated production of inflammatory cytokines in the liver of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) The frequency (left and upper right) and the absolute number (lower right) of activated CD4+ T cells (CD44hiCD62Llow) derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0 and 7 after infection with T. congolense. (B) Production of IFN-γ, IL-12p40, and TNF-α in the supernatant fluids of cultured liver leukocytes purified from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. (C) The frequency (left and upper right) and the absolute number (lower right) of IFN-γ-producing CD4+ T cells derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0, 7 and 10 after infection with T. congolense following 12 h in vitro restimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4519326&req=5

ppat.1005065.g005: Enhanced activation of CD4+ T cells and elevated production of inflammatory cytokines in the liver of IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) The frequency (left and upper right) and the absolute number (lower right) of activated CD4+ T cells (CD44hiCD62Llow) derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0 and 7 after infection with T. congolense. (B) Production of IFN-γ, IL-12p40, and TNF-α in the supernatant fluids of cultured liver leukocytes purified from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. (C) The frequency (left and upper right) and the absolute number (lower right) of IFN-γ-producing CD4+ T cells derived from the liver of IL-27R-/- and wild-type mice (n = 3) on day 0, 7 and 10 after infection with T. congolense following 12 h in vitro restimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
Mentions: Because early mortality of IL-27R-/- mice infected with African trypanosomes was associated with severe liver pathology without impaired secretion of IL-10 as shown above and because IL-27 has been shown to mainly regulate T cell, particularly CD4+ T cell activation during infection with intracellular pathogens [38–42], we next characterized CD4+ T cell responses in the liver of IL-27R-/- mice during infection with T. congolense. We found that the frequency and the absolute number of activated hepatic CD4+ T cells (CD44hiCD62Llow) were significantly higher in IL-27R-/- mice infected with T. congolense, compared to infected wild-type mice (p<0.01, Fig 5A). The production of IFN-γ, IL-12p40, and TNF-α by cultured liver leukocytes from infected IL-27R-/- mice was significantly higher than production of these cytokines by liver leukocytes from infected wild-type mice (p<0.001, <0.01 or <0.05, Fig 5B). In particular, the production of IFN-γ was enhanced by 4–8 folds in the liver leukocyte cultures of infected IL-27R-/- mice (Fig 5B). Thus, we further evaluated the activation of liver CD4+ T cells by examining their secretions of IFN-γ using single cell analysis. A small and similar percentage and absolute number of CD4+ T cells from uninfected wild-type and IL-27R-/- mice secreted IFN-γ after 12 h stimulation with Cell Stimulation Cocktail (containing PMA, ionomycin, and protein transport inhibitors). In contrast, by day 7 and 10 post infection significantly higher percentage and absolute number of IFN-γ-producing CD4+ T cells were detected in IL-27R-/- mice as compared to wild-type cohorts (Fig 5C). Collectively, these data suggested that the early mortality of IL-27R-/- mice infected with African trypanosomes was associated with exacerbated Th1-mediated immune responses with overactivation of CD4+ T cells.

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