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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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Serum cytokine levels in T. gondii–infected mice treated with anti–IL-10R mAb in the presence or absence of concurrent CD4 T cell depletion. Uninfected or infected mice treated on days −2 and +2 relative to the time of infection with control mAb, anti–IL-10R mAb, anti–IL-10R plus anti-CD4 mAb, or anti-CD4 mAb only were bled on day 8 after infection. Serum concentrations of IL-12, IFN-γ, and IL-10 were measured by ELISA. Bars represent the mean ± SEM of the cytokine levels in three to five mice per group from one representative of two experiments performed. *, P < 0.05; **, P < 0.01; NS, P = 0.2.
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fig2: Serum cytokine levels in T. gondii–infected mice treated with anti–IL-10R mAb in the presence or absence of concurrent CD4 T cell depletion. Uninfected or infected mice treated on days −2 and +2 relative to the time of infection with control mAb, anti–IL-10R mAb, anti–IL-10R plus anti-CD4 mAb, or anti-CD4 mAb only were bled on day 8 after infection. Serum concentrations of IL-12, IFN-γ, and IL-10 were measured by ELISA. Bars represent the mean ± SEM of the cytokine levels in three to five mice per group from one representative of two experiments performed. *, P < 0.05; **, P < 0.01; NS, P = 0.2.

Mentions: As a consequence of T. gondii exposure, serum levels of IL-12p40 and IFN-γ transiently increase and peak on day 7 after infection (21). Treatment with anti–IL-10R, but not anti-CD25 (not depicted), mAb resulted in further elevation of these two cytokines (Fig. 2). Anti–IL-10R mAb administration also dramatically augmented levels of IL-10, probably as a consequence of blockade of cytokine consumption. To assess the contribution of CD4 T lymphocytes in the observed serum cytokine responses, groups of infected mice were treated in parallel with either anti–IL-10R plus anti-CD4 mAb or anti-CD4 mAb alone. Simultaneous depletion of CD4+ T cells completely abrogated the increases in IFN-γ and IL-10 resulting from anti–IL-10R mAb treatment, suggesting that Th lymphocytes serve as a major source of these two cytokines. In contrast, ablation of CD4+ T lymphocytes caused only a minor decrease in serum IL-12 levels in the same anti–IL-10R mAb–treated animals. Unexpectedly, anti-CD4 mAb depletion induced a sharp increase in IL-12 in infected mice in the absence of concurrent anti–IL-10R mAb administration (Fig. 2). The latter findings suggested that during T. gondii infection CD4+ T cells suppress rather than promote IL-12 production.


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)

Serum cytokine levels in T. gondii–infected mice treated with anti–IL-10R mAb in the presence or absence of concurrent CD4 T cell depletion. Uninfected or infected mice treated on days −2 and +2 relative to the time of infection with control mAb, anti–IL-10R mAb, anti–IL-10R plus anti-CD4 mAb, or anti-CD4 mAb only were bled on day 8 after infection. Serum concentrations of IL-12, IFN-γ, and IL-10 were measured by ELISA. Bars represent the mean ± SEM of the cytokine levels in three to five mice per group from one representative of two experiments performed. *, P < 0.05; **, P < 0.01; NS, P = 0.2.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Serum cytokine levels in T. gondii–infected mice treated with anti–IL-10R mAb in the presence or absence of concurrent CD4 T cell depletion. Uninfected or infected mice treated on days −2 and +2 relative to the time of infection with control mAb, anti–IL-10R mAb, anti–IL-10R plus anti-CD4 mAb, or anti-CD4 mAb only were bled on day 8 after infection. Serum concentrations of IL-12, IFN-γ, and IL-10 were measured by ELISA. Bars represent the mean ± SEM of the cytokine levels in three to five mice per group from one representative of two experiments performed. *, P < 0.05; **, P < 0.01; NS, P = 0.2.
Mentions: As a consequence of T. gondii exposure, serum levels of IL-12p40 and IFN-γ transiently increase and peak on day 7 after infection (21). Treatment with anti–IL-10R, but not anti-CD25 (not depicted), mAb resulted in further elevation of these two cytokines (Fig. 2). Anti–IL-10R mAb administration also dramatically augmented levels of IL-10, probably as a consequence of blockade of cytokine consumption. To assess the contribution of CD4 T lymphocytes in the observed serum cytokine responses, groups of infected mice were treated in parallel with either anti–IL-10R plus anti-CD4 mAb or anti-CD4 mAb alone. Simultaneous depletion of CD4+ T cells completely abrogated the increases in IFN-γ and IL-10 resulting from anti–IL-10R mAb treatment, suggesting that Th lymphocytes serve as a major source of these two cytokines. In contrast, ablation of CD4+ T lymphocytes caused only a minor decrease in serum IL-12 levels in the same anti–IL-10R mAb–treated animals. Unexpectedly, anti-CD4 mAb depletion induced a sharp increase in IL-12 in infected mice in the absence of concurrent anti–IL-10R mAb administration (Fig. 2). The latter findings suggested that during T. gondii infection CD4+ T cells suppress rather than promote IL-12 production.

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