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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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Transfer of IL-10+/+, but not IL-10−/−, CD4+ cells down-regulates IL-12 production in vivo and promotes survival of T. gondii–infected RAG × IL-10 KO mice. 15 × 106 MACS-purified CD4 cells from either WT or IL-10 KO naive mice were adoptively transferred into RAG × IL-10 KO recipients. 7 d later, reconstituted (n = 5) and nonreconstituted (n = 4) RAG × IL-10 KO animals were inoculated i.p. with 20 pepsin-treated ME-49 cysts. (A) Mice were bled on day 8 after infection, and serum concentrations of IL-12 and IFN-γ were measured by ELISA. (B) Cumulative survival of each group of animals. The data shown are the pooled results from two independent experiments. *, P < 0.002; **, P < 0.001; NS, P = 0.3.
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fig3: Transfer of IL-10+/+, but not IL-10−/−, CD4+ cells down-regulates IL-12 production in vivo and promotes survival of T. gondii–infected RAG × IL-10 KO mice. 15 × 106 MACS-purified CD4 cells from either WT or IL-10 KO naive mice were adoptively transferred into RAG × IL-10 KO recipients. 7 d later, reconstituted (n = 5) and nonreconstituted (n = 4) RAG × IL-10 KO animals were inoculated i.p. with 20 pepsin-treated ME-49 cysts. (A) Mice were bled on day 8 after infection, and serum concentrations of IL-12 and IFN-γ were measured by ELISA. (B) Cumulative survival of each group of animals. The data shown are the pooled results from two independent experiments. *, P < 0.002; **, P < 0.001; NS, P = 0.3.

Mentions: To directly test this hypothesis, we reconstituted RAG × IL-10 double KO mice with either WT or IL-10–deficient CD4+ T cells from naive donors and infected them with T. gondii 7 d later. When serum cytokine levels were measured 1 wk later, the recipients of WT, but not IL-10 KO, CD4+ T cells showed decreased IL-12 levels relative to the nonreconstituted controls animals (Fig. 3 A). Although the WT CD4+ T cell–reconstituted mice displayed significantly increased IFN-γ production relative to nonreconstituted animals, the levels observed were threefold lower than those measured in the recipients of IL-10 KO CD4+ T cells, probably as a consequence of the decreased IL-12 production in the former mice. The uncontrolled IFN-γ production observed in the RAG × IL-10 KO mice reconstituted with IL-10 KO CD4+ cells correlated with a reduction in survival relative to the infected nonreconstituted animals (Fig. 3 B). In contrast, RAG × IL-10 KO recipients of WT CD4+ T cells were protected against T. gondii–induced lethality.


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)

Transfer of IL-10+/+, but not IL-10−/−, CD4+ cells down-regulates IL-12 production in vivo and promotes survival of T. gondii–infected RAG × IL-10 KO mice. 15 × 106 MACS-purified CD4 cells from either WT or IL-10 KO naive mice were adoptively transferred into RAG × IL-10 KO recipients. 7 d later, reconstituted (n = 5) and nonreconstituted (n = 4) RAG × IL-10 KO animals were inoculated i.p. with 20 pepsin-treated ME-49 cysts. (A) Mice were bled on day 8 after infection, and serum concentrations of IL-12 and IFN-γ were measured by ELISA. (B) Cumulative survival of each group of animals. The data shown are the pooled results from two independent experiments. *, P < 0.002; **, P < 0.001; NS, P = 0.3.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Transfer of IL-10+/+, but not IL-10−/−, CD4+ cells down-regulates IL-12 production in vivo and promotes survival of T. gondii–infected RAG × IL-10 KO mice. 15 × 106 MACS-purified CD4 cells from either WT or IL-10 KO naive mice were adoptively transferred into RAG × IL-10 KO recipients. 7 d later, reconstituted (n = 5) and nonreconstituted (n = 4) RAG × IL-10 KO animals were inoculated i.p. with 20 pepsin-treated ME-49 cysts. (A) Mice were bled on day 8 after infection, and serum concentrations of IL-12 and IFN-γ were measured by ELISA. (B) Cumulative survival of each group of animals. The data shown are the pooled results from two independent experiments. *, P < 0.002; **, P < 0.001; NS, P = 0.3.
Mentions: To directly test this hypothesis, we reconstituted RAG × IL-10 double KO mice with either WT or IL-10–deficient CD4+ T cells from naive donors and infected them with T. gondii 7 d later. When serum cytokine levels were measured 1 wk later, the recipients of WT, but not IL-10 KO, CD4+ T cells showed decreased IL-12 levels relative to the nonreconstituted controls animals (Fig. 3 A). Although the WT CD4+ T cell–reconstituted mice displayed significantly increased IFN-γ production relative to nonreconstituted animals, the levels observed were threefold lower than those measured in the recipients of IL-10 KO CD4+ T cells, probably as a consequence of the decreased IL-12 production in the former mice. The uncontrolled IFN-γ production observed in the RAG × IL-10 KO mice reconstituted with IL-10 KO CD4+ cells correlated with a reduction in survival relative to the infected nonreconstituted animals (Fig. 3 B). In contrast, RAG × IL-10 KO recipients of WT CD4+ T cells were protected against T. gondii–induced lethality.

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