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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 negative feedback regulation of Th1 responses. Tg4 mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic DCs were isolated from both untreated and peptide-treated Tg4 mice that were administered 100 µg of MBP Ac1-9[4Y] 3 h previously. CD4+ T cells positively selected from untreated Tg4 mouse spleens were cultured at 5 × 104 per well in the presence of a twofold titration of irradiated DCs at a ratio ranging from 80:1 to 10:1 and 10 µg/ml of Ac1-9[4K]. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B) Cytokine responses of CD4+ T cell from the 10:1 cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-12) after in vitro restimulation. Results are depicted as the mean cytokine production in ng/ml of supernatant ± SEM. Data are representative of two individual experiments.
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fig8: Role of IL-10 in negative feedback regulation of Th1 responses. Tg4 mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic DCs were isolated from both untreated and peptide-treated Tg4 mice that were administered 100 µg of MBP Ac1-9[4Y] 3 h previously. CD4+ T cells positively selected from untreated Tg4 mouse spleens were cultured at 5 × 104 per well in the presence of a twofold titration of irradiated DCs at a ratio ranging from 80:1 to 10:1 and 10 µg/ml of Ac1-9[4K]. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B) Cytokine responses of CD4+ T cell from the 10:1 cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-12) after in vitro restimulation. Results are depicted as the mean cytokine production in ng/ml of supernatant ± SEM. Data are representative of two individual experiments.

Mentions: To demonstrate the in vivo relevance of peptide-induced IL-10 T reg cell–DC interactions, the functional properties of DCs isolated from either naive Tg4 mice or mice rendered tolerant by i.n. peptide treatment were further evaluated. Compared with splenic DCs from naive mice, DCs from tolerant mice were less effective at inducing naive CD4+ T cell proliferation in vitro (Fig. 8 A). Furthermore, splenic DCs from peptide-treated mice failed to support secretion of Th1-associated cytokines by these cells (Fig. 8 B). The defective induction of IL-2 and IFN-γ secretion by naive CD4+ T cells in the co-cultures correlated with markedly reduced IL-12 secretion (Fig. 8 B). The suppressive properties of IL-10 T reg cells therefore extend to DC function as well as phenotype. Collectively, our results reveal a classical negative feedback loop whereby chronically activated Th1 cells differentiate into IL-10 T reg cells capable of regulating DC function, thus preventing further generation of Th1 cells.


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 negative feedback regulation of Th1 responses. Tg4 mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic DCs were isolated from both untreated and peptide-treated Tg4 mice that were administered 100 µg of MBP Ac1-9[4Y] 3 h previously. CD4+ T cells positively selected from untreated Tg4 mouse spleens were cultured at 5 × 104 per well in the presence of a twofold titration of irradiated DCs at a ratio ranging from 80:1 to 10:1 and 10 µg/ml of Ac1-9[4K]. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B) Cytokine responses of CD4+ T cell from the 10:1 cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-12) after in vitro restimulation. Results are depicted as the mean cytokine production in ng/ml of supernatant ± SEM. Data are representative of two individual experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig8: Role of IL-10 in negative feedback regulation of Th1 responses. Tg4 mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y]. Splenic DCs were isolated from both untreated and peptide-treated Tg4 mice that were administered 100 µg of MBP Ac1-9[4Y] 3 h previously. CD4+ T cells positively selected from untreated Tg4 mouse spleens were cultured at 5 × 104 per well in the presence of a twofold titration of irradiated DCs at a ratio ranging from 80:1 to 10:1 and 10 µg/ml of Ac1-9[4K]. (A) Proliferative responses were measured at 72 h by 3[H]thymidine incorporation. Results are depicted as the mean thymidine incorporation ± SEM. (B) Cytokine responses of CD4+ T cell from the 10:1 cultures were measured by ELISA at 24 h (IL-2) and 72 h (IFN-γ and IL-12) after in vitro restimulation. Results are depicted as the mean cytokine production in ng/ml of supernatant ± SEM. Data are representative of two individual experiments.
Mentions: To demonstrate the in vivo relevance of peptide-induced IL-10 T reg cell–DC interactions, the functional properties of DCs isolated from either naive Tg4 mice or mice rendered tolerant by i.n. peptide treatment were further evaluated. Compared with splenic DCs from naive mice, DCs from tolerant mice were less effective at inducing naive CD4+ T cell proliferation in vitro (Fig. 8 A). Furthermore, splenic DCs from peptide-treated mice failed to support secretion of Th1-associated cytokines by these cells (Fig. 8 B). The defective induction of IL-2 and IFN-γ secretion by naive CD4+ T cells in the co-cultures correlated with markedly reduced IL-12 secretion (Fig. 8 B). The suppressive properties of IL-10 T reg cells therefore extend to DC function as well as phenotype. Collectively, our results reveal a classical negative feedback loop whereby chronically activated Th1 cells differentiate into IL-10 T reg cells capable of regulating DC function, thus preventing further generation of Th1 cells.

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