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Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells.

Gabrysová L, Nicolson KS, Streeter HB, Verhagen J, Sabatos-Peyton CA, Morgan DJ, Wraith DC - J. Exp. Med. (2009)

Bottom Line: Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-gamma to the regulatory cytokine IL-10.IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology.These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, University of Bristol School of Medical Sciences, Bristol BS8 1TD, England, UK. Leona.Gabrysova@bristol.ac.uk

ABSTRACT
Regulation of the immune response to self- and foreign antigens is vitally important for limiting immune pathology associated with both infections and hypersensitivity conditions. Control of autoimmune conditions can be reinforced by tolerance induction with peptide epitopes, but the mechanism is not currently understood. Repetitive intranasal administration of soluble peptide induces peripheral tolerance in myelin basic protein (MBP)-specific TCR transgenic mice. This is characterized by the presence of anergic, interleukin (IL)-10-secreting CD4(+) T cells with regulatory function (IL-10 T reg cells). The differentiation pathway of peptide-induced IL-10 T reg cells was investigated. CD4(+) T cells became anergic after their second encounter with a high-affinity MBP peptide analogue. Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-gamma to the regulatory cytokine IL-10. Nevertheless, IL-10 T reg cells retained the capacity to produce IFN-gamma and concomitantly expressed T-bet, demonstrating their Th1 origin. IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology. These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.

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Role of IL-10 in down-regulation of Th1 cytokines in tolerance. Tg4 and Tg4 IL-10−/− mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic CD4+ T cells were positively selected from either untreated Tg4 or peptide-treated Tg4 and Tg4 IL-10−/− mice 3 d after the last peptide treatment. 5 × 104 CD4+ T cells per well were cultured with 105 irradiated B10.PL splenocytes as APCs in the presence of a 10-fold titration of MBP Ac1-9[4K], ranging from 0.1 to 100 µg/ml. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B–D) Cytokine responses of CD4+ T cells from the above cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-10) after in vitro restimulation. Results are expressed as the mean cytokine production in nanogram/milliliter of supernatant ± SEM. Data are representative of at least three individual experiments.
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fig5: Role of IL-10 in down-regulation of Th1 cytokines in tolerance. Tg4 and Tg4 IL-10−/− mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic CD4+ T cells were positively selected from either untreated Tg4 or peptide-treated Tg4 and Tg4 IL-10−/− mice 3 d after the last peptide treatment. 5 × 104 CD4+ T cells per well were cultured with 105 irradiated B10.PL splenocytes as APCs in the presence of a 10-fold titration of MBP Ac1-9[4K], ranging from 0.1 to 100 µg/ml. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B–D) Cytokine responses of CD4+ T cells from the above cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-10) after in vitro restimulation. Results are expressed as the mean cytokine production in nanogram/milliliter of supernatant ± SEM. Data are representative of at least three individual experiments.

Mentions: The role of IL-10 in the induction of tolerance has been addressed by assessing the effect of repeated i.n. peptide treatment on CD4+ T cells from Tg4 IL-10−/− mice. A comparison of in vitro proliferative responses from peptide-treated Tg4 or Tg4 IL-10−/− mice revealed that CD4+ T cells from both mouse strains were anergic (Fig. 5 A). This correlated with a marked reduction in IL-2 production, which is consistent with clonal anergy (Fig. 5 B). Despite their anergic state, however, CD4+ T cells from peptide-treated Tg4 IL-10−/− mice secreted IFN-γ at levels equivalent or higher than CD4+ T cells from untreated Tg4 mice (Fig. 5 C). Furthermore, increased levels of IFN-γ, but not IL-2, were sustained in sera from peptide-treated Tg4 IL-10−/− mice (Fig. S2). In contrast, IL-10, as opposed to IFN-γ, was detected in CD4+ T cell cultures from peptide-treated, control Tg4 mice (Fig. 5, C and D). These results suggest that treatment with i.n. peptide in the absence of IL-10 results in priming rather than tolerance induction, demonstrating the role for IL-10 in negative feedback regulation of Th1 responses.


Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells.

Gabrysová L, Nicolson KS, Streeter HB, Verhagen J, Sabatos-Peyton CA, Morgan DJ, Wraith DC - J. Exp. Med. (2009)

Role of IL-10 in down-regulation of Th1 cytokines in tolerance. Tg4 and Tg4 IL-10−/− mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic CD4+ T cells were positively selected from either untreated Tg4 or peptide-treated Tg4 and Tg4 IL-10−/− mice 3 d after the last peptide treatment. 5 × 104 CD4+ T cells per well were cultured with 105 irradiated B10.PL splenocytes as APCs in the presence of a 10-fold titration of MBP Ac1-9[4K], ranging from 0.1 to 100 µg/ml. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B–D) Cytokine responses of CD4+ T cells from the above cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-10) after in vitro restimulation. Results are expressed as the mean cytokine production in nanogram/milliliter of supernatant ± SEM. Data are representative of at least three individual experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC2722173&req=5

fig5: Role of IL-10 in down-regulation of Th1 cytokines in tolerance. Tg4 and Tg4 IL-10−/− mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic CD4+ T cells were positively selected from either untreated Tg4 or peptide-treated Tg4 and Tg4 IL-10−/− mice 3 d after the last peptide treatment. 5 × 104 CD4+ T cells per well were cultured with 105 irradiated B10.PL splenocytes as APCs in the presence of a 10-fold titration of MBP Ac1-9[4K], ranging from 0.1 to 100 µg/ml. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B–D) Cytokine responses of CD4+ T cells from the above cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-10) after in vitro restimulation. Results are expressed as the mean cytokine production in nanogram/milliliter of supernatant ± SEM. Data are representative of at least three individual experiments.
Mentions: The role of IL-10 in the induction of tolerance has been addressed by assessing the effect of repeated i.n. peptide treatment on CD4+ T cells from Tg4 IL-10−/− mice. A comparison of in vitro proliferative responses from peptide-treated Tg4 or Tg4 IL-10−/− mice revealed that CD4+ T cells from both mouse strains were anergic (Fig. 5 A). This correlated with a marked reduction in IL-2 production, which is consistent with clonal anergy (Fig. 5 B). Despite their anergic state, however, CD4+ T cells from peptide-treated Tg4 IL-10−/− mice secreted IFN-γ at levels equivalent or higher than CD4+ T cells from untreated Tg4 mice (Fig. 5 C). Furthermore, increased levels of IFN-γ, but not IL-2, were sustained in sera from peptide-treated Tg4 IL-10−/− mice (Fig. S2). In contrast, IL-10, as opposed to IFN-γ, was detected in CD4+ T cell cultures from peptide-treated, control Tg4 mice (Fig. 5, C and D). These results suggest that treatment with i.n. peptide in the absence of IL-10 results in priming rather than tolerance induction, demonstrating the role for IL-10 in negative feedback regulation of Th1 responses.

Bottom Line: Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-gamma to the regulatory cytokine IL-10.IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology.These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, University of Bristol School of Medical Sciences, Bristol BS8 1TD, England, UK. Leona.Gabrysova@bristol.ac.uk

ABSTRACT
Regulation of the immune response to self- and foreign antigens is vitally important for limiting immune pathology associated with both infections and hypersensitivity conditions. Control of autoimmune conditions can be reinforced by tolerance induction with peptide epitopes, but the mechanism is not currently understood. Repetitive intranasal administration of soluble peptide induces peripheral tolerance in myelin basic protein (MBP)-specific TCR transgenic mice. This is characterized by the presence of anergic, interleukin (IL)-10-secreting CD4(+) T cells with regulatory function (IL-10 T reg cells). The differentiation pathway of peptide-induced IL-10 T reg cells was investigated. CD4(+) T cells became anergic after their second encounter with a high-affinity MBP peptide analogue. Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-gamma to the regulatory cytokine IL-10. Nevertheless, IL-10 T reg cells retained the capacity to produce IFN-gamma and concomitantly expressed T-bet, demonstrating their Th1 origin. IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology. These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.

Show MeSH
Related in: MedlinePlus