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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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Redundancy of non-T cell–derived IL-10 in IL-10 T reg cell differentiation. Negatively selected Tg4 CD4+ T cells at 2 × 107 per mouse were adoptively transferred into either B10.PL or B10.PL IL-10−/− recipients. 7 d later, mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y] at 3–4 d intervals or left untreated as controls. Spleens from peptide-treated recipient mice were collected 3 d after the last peptide treatment. Tg4 CD4+ T cells were selected by culturing with 10 µg/ml of Ac1-9[4K] and rhIL-2 for 7 d and stained for surface Vβ8 and intracellular IFN-γ or IL-10 after additional restimulation with PMA and ionomycin. The depicted contour plots are gated on Vβ8+ T cells with quadrants based on isotype controls. Data are representative of at least three individual experiments.
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fig6: Redundancy of non-T cell–derived IL-10 in IL-10 T reg cell differentiation. Negatively selected Tg4 CD4+ T cells at 2 × 107 per mouse were adoptively transferred into either B10.PL or B10.PL IL-10−/− recipients. 7 d later, mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y] at 3–4 d intervals or left untreated as controls. Spleens from peptide-treated recipient mice were collected 3 d after the last peptide treatment. Tg4 CD4+ T cells were selected by culturing with 10 µg/ml of Ac1-9[4K] and rhIL-2 for 7 d and stained for surface Vβ8 and intracellular IFN-γ or IL-10 after additional restimulation with PMA and ionomycin. The depicted contour plots are gated on Vβ8+ T cells with quadrants based on isotype controls. Data are representative of at least three individual experiments.

Mentions: Previous studies have shown that exogenous IL-10 encourages differentiation of IL-10–secreting T reg cells in vitro (Groux et al., 1996). We used an adoptive transfer model to investigate whether differentiation of peptide-induced IL-10 T reg cells depends on IL-10 secretion by other cells such as APCs. As shown in Fig. 6, transfer of Tg4 CD4+ T cells into B10.PL recipients followed by repeated peptide treatment led to the differentiation of IFN-γ–producing Tg4 cells, up to 8% of which coproduced IL-10 after activation with PMA and ionomycin. Transfer of Tg4 CD4+ T cells into IL-10–deficient B10.PL recipient mice allowed the differentiation of a population of cells with a similar proportion coproducing IFN-γ and IL-10, as well as a markedly distinct population (22%) producing IL-10 only. Neither group of control mice produced significant amounts of IL-10, and levels of IFN-γ were reduced (Fig. 6, bottom). IL-4 was not detected in either set of recipients (unpublished data). These data suggest that there is no requirement for IL-10 from non–T cells for the differentiation of IL-10 T reg cells. In fact, the ability of non–T cells to secrete IL-10 may limit the differentiation of IL-10 T reg 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)

Redundancy of non-T cell–derived IL-10 in IL-10 T reg cell differentiation. Negatively selected Tg4 CD4+ T cells at 2 × 107 per mouse were adoptively transferred into either B10.PL or B10.PL IL-10−/− recipients. 7 d later, mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y] at 3–4 d intervals or left untreated as controls. Spleens from peptide-treated recipient mice were collected 3 d after the last peptide treatment. Tg4 CD4+ T cells were selected by culturing with 10 µg/ml of Ac1-9[4K] and rhIL-2 for 7 d and stained for surface Vβ8 and intracellular IFN-γ or IL-10 after additional restimulation with PMA and ionomycin. The depicted contour plots are gated on Vβ8+ T cells with quadrants based on isotype controls. Data are representative of at least three individual experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig6: Redundancy of non-T cell–derived IL-10 in IL-10 T reg cell differentiation. Negatively selected Tg4 CD4+ T cells at 2 × 107 per mouse were adoptively transferred into either B10.PL or B10.PL IL-10−/− recipients. 7 d later, mice were treated with a minimum of 10 i.n. doses of MBP Ac1-9[4Y] at 3–4 d intervals or left untreated as controls. Spleens from peptide-treated recipient mice were collected 3 d after the last peptide treatment. Tg4 CD4+ T cells were selected by culturing with 10 µg/ml of Ac1-9[4K] and rhIL-2 for 7 d and stained for surface Vβ8 and intracellular IFN-γ or IL-10 after additional restimulation with PMA and ionomycin. The depicted contour plots are gated on Vβ8+ T cells with quadrants based on isotype controls. Data are representative of at least three individual experiments.
Mentions: Previous studies have shown that exogenous IL-10 encourages differentiation of IL-10–secreting T reg cells in vitro (Groux et al., 1996). We used an adoptive transfer model to investigate whether differentiation of peptide-induced IL-10 T reg cells depends on IL-10 secretion by other cells such as APCs. As shown in Fig. 6, transfer of Tg4 CD4+ T cells into B10.PL recipients followed by repeated peptide treatment led to the differentiation of IFN-γ–producing Tg4 cells, up to 8% of which coproduced IL-10 after activation with PMA and ionomycin. Transfer of Tg4 CD4+ T cells into IL-10–deficient B10.PL recipient mice allowed the differentiation of a population of cells with a similar proportion coproducing IFN-γ and IL-10, as well as a markedly distinct population (22%) producing IL-10 only. Neither group of control mice produced significant amounts of IL-10, and levels of IFN-γ were reduced (Fig. 6, bottom). IL-4 was not detected in either set of recipients (unpublished data). These data suggest that there is no requirement for IL-10 from non–T cells for the differentiation of IL-10 T reg cells. In fact, the ability of non–T cells to secrete IL-10 may limit the differentiation of IL-10 T reg 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