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Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.

Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M, Wynn TA, Kamanaka M, Flavell RA, Sher A - J. Exp. Med. (2007)

Bottom Line: Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals.Further analysis revealed that the same IL-10(+)IFN-gamma(gamma) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells.These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Section and 2Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. DJankovic@niaid.nih.gov

ABSTRACT
Although interferon gamma (IFN-gamma) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-gamma effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10(+)IFN-gamma(gamma) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-gamma, IL-10 production could be stimulated in IL-10(-)IFN-gamma(+) cells by further activation in vitro. In addition, experiments with T. gondii-specific IL-10(+)IFN-gamma(+) CD4 clones revealed that although IFN-gamma expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.

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IL-10R signaling is required for host survival during both acute and chronic infection with an avirulent strain of T. gondii. WT mice inoculated i.p. with 20 ME-49 cysts were treated with control (open circles; n = 10), anti–IL-10R (closed circles; n = 10), or anti-CD25 (open triangles; n = 10) mAbs either at days −2 and +2 (A, C, and E) or at days +28, 30, and 33 (B, D, and F). Survival (A and B) and body weight (C and D) of the infected mice was then monitored. In addition, levels of hepatic ASTs (E and F) were measured in sera of individual mice before (hatched bars) or after treatment with the control (open bars) or anti–IL-10R (shaded bars) mAbs. The results shown represent the mean ± SD for each group. Comparable results were obtained in two additional experiments.
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fig1: IL-10R signaling is required for host survival during both acute and chronic infection with an avirulent strain of T. gondii. WT mice inoculated i.p. with 20 ME-49 cysts were treated with control (open circles; n = 10), anti–IL-10R (closed circles; n = 10), or anti-CD25 (open triangles; n = 10) mAbs either at days −2 and +2 (A, C, and E) or at days +28, 30, and 33 (B, D, and F). Survival (A and B) and body weight (C and D) of the infected mice was then monitored. In addition, levels of hepatic ASTs (E and F) were measured in sera of individual mice before (hatched bars) or after treatment with the control (open bars) or anti–IL-10R (shaded bars) mAbs. The results shown represent the mean ± SD for each group. Comparable results were obtained in two additional experiments.

Mentions: In contrast to WT animals, IL-10 KO mice infected with avirulent strains of T. gondii display acute tissue pathology and mortality associated with overproduction of proinflammatory cytokines (22, 26, 27, 30). To determine whether this phenotype results solely from the absence of active IL-10–mediated suppression as opposed to indirect developmental effects caused by the lack of this cytokine gene, we first asked if IL-10–dependent signaling is also necessary for survival of infected WT animals and, if yes, whether this requirement additionally extends to chronically infected hosts. To do so, we treated WT mice beginning either 2 d before or 28 d after infection with a blocking anti–IL-10R mAb and monitored their survival. In contrast to animals injected with control mAb, which survived for the entire period of the experiment, mice treated with anti–IL-10R mAb at the time of infection rapidly succumbed, recapitulating the phenotype originally observed in infected IL-10 KO animals (Fig. 1 A). The same kinetics of mortality were observed when mice were treated with anti–IL-10R mAb during the chronic phase, demonstrating a protective role of the cytokine once latent infection has been established (Fig. 1 B). In both situations, the decreased survival of the anti–IL-10R mAb-treated mice was preceded by significant weight loss (Fig. 1, C and D) and hepatic dysfunction as indicated by increased levels of serum aspartate aminotransferase (AST; Fig. 1, E and F), consistent with previous observations in infected IL-10 KO animals (22).


Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.

Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M, Wynn TA, Kamanaka M, Flavell RA, Sher A - J. Exp. Med. (2007)

IL-10R signaling is required for host survival during both acute and chronic infection with an avirulent strain of T. gondii. WT mice inoculated i.p. with 20 ME-49 cysts were treated with control (open circles; n = 10), anti–IL-10R (closed circles; n = 10), or anti-CD25 (open triangles; n = 10) mAbs either at days −2 and +2 (A, C, and E) or at days +28, 30, and 33 (B, D, and F). Survival (A and B) and body weight (C and D) of the infected mice was then monitored. In addition, levels of hepatic ASTs (E and F) were measured in sera of individual mice before (hatched bars) or after treatment with the control (open bars) or anti–IL-10R (shaded bars) mAbs. The results shown represent the mean ± SD for each group. Comparable results were obtained in two additional experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118735&req=5

fig1: IL-10R signaling is required for host survival during both acute and chronic infection with an avirulent strain of T. gondii. WT mice inoculated i.p. with 20 ME-49 cysts were treated with control (open circles; n = 10), anti–IL-10R (closed circles; n = 10), or anti-CD25 (open triangles; n = 10) mAbs either at days −2 and +2 (A, C, and E) or at days +28, 30, and 33 (B, D, and F). Survival (A and B) and body weight (C and D) of the infected mice was then monitored. In addition, levels of hepatic ASTs (E and F) were measured in sera of individual mice before (hatched bars) or after treatment with the control (open bars) or anti–IL-10R (shaded bars) mAbs. The results shown represent the mean ± SD for each group. Comparable results were obtained in two additional experiments.
Mentions: In contrast to WT animals, IL-10 KO mice infected with avirulent strains of T. gondii display acute tissue pathology and mortality associated with overproduction of proinflammatory cytokines (22, 26, 27, 30). To determine whether this phenotype results solely from the absence of active IL-10–mediated suppression as opposed to indirect developmental effects caused by the lack of this cytokine gene, we first asked if IL-10–dependent signaling is also necessary for survival of infected WT animals and, if yes, whether this requirement additionally extends to chronically infected hosts. To do so, we treated WT mice beginning either 2 d before or 28 d after infection with a blocking anti–IL-10R mAb and monitored their survival. In contrast to animals injected with control mAb, which survived for the entire period of the experiment, mice treated with anti–IL-10R mAb at the time of infection rapidly succumbed, recapitulating the phenotype originally observed in infected IL-10 KO animals (Fig. 1 A). The same kinetics of mortality were observed when mice were treated with anti–IL-10R mAb during the chronic phase, demonstrating a protective role of the cytokine once latent infection has been established (Fig. 1 B). In both situations, the decreased survival of the anti–IL-10R mAb-treated mice was preceded by significant weight loss (Fig. 1, C and D) and hepatic dysfunction as indicated by increased levels of serum aspartate aminotransferase (AST; Fig. 1, E and F), consistent with previous observations in infected IL-10 KO animals (22).

Bottom Line: Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals.Further analysis revealed that the same IL-10(+)IFN-gamma(gamma) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells.These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Section and 2Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. DJankovic@niaid.nih.gov

ABSTRACT
Although interferon gamma (IFN-gamma) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-gamma effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10(+)IFN-gamma(gamma) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-gamma, IL-10 production could be stimulated in IL-10(-)IFN-gamma(+) cells by further activation in vitro. In addition, experiments with T. gondii-specific IL-10(+)IFN-gamma(+) CD4 clones revealed that although IFN-gamma expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.

Show MeSH
Related in: MedlinePlus