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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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Related in: MedlinePlus

Changes in serum cytokine profile over the course of tolerance induction. Tg4 Rag1−/− mice were bled before treatment and after each successive i.n. MBP Ac1-9[4Y] administration. Serum concentrations of IL-2, IL-10, IFN-γ, IL-17, IL-4, and IL-5 were measured by cytometric bead assay. Results show the mean serum cytokine concentration of six to eight mice per treatment group on pooled data from two separate experiments.
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fig1: Changes in serum cytokine profile over the course of tolerance induction. Tg4 Rag1−/− mice were bled before treatment and after each successive i.n. MBP Ac1-9[4Y] administration. Serum concentrations of IL-2, IL-10, IFN-γ, IL-17, IL-4, and IL-5 were measured by cytometric bead assay. Results show the mean serum cytokine concentration of six to eight mice per treatment group on pooled data from two separate experiments.

Mentions: Peripheral tolerance is induced in the Tg4 TCR transgenic mouse by repeated i.n. administration of antigenic peptide (Burkhart et al., 1999). This results in the generation of IL-10–secreting T reg cells capable of suppressing immune responses in vivo (Sundstedt et al., 2003). To investigate the differentiation pathway of peptide-induced IL-10 T reg cells, we first sought to determine changes in the serum cytokine profile over the course of tolerization in Tg4 Rag1−/− mice. Serum concentrations of IL-2, IFN-γ, IL-17, IL-4, IL-5, and IL-10 were assessed at 2 h after successive i.n. peptide administration (Fig. 1). The 2-h time point represents the peak of cytokine secretion, as determined previously (Sundstedt et al., 2003). As shown in Fig. 1, distinct patterns of serum cytokine levels emerged. The Th1 cytokines IL-2 and IFN-γ followed a similar profile, with the mean serum levels peaking after the second i.n. peptide treatment and decreasing to near background thereafter. IL-17 secretion was delayed relative to the Th1 cytokines with a peak after the fourth i.n. peptide administration. In marked contrast, the Th2 cytokines IL-4 and IL-5 were secreted at only very low levels over the entire course of i.n. peptide treatment. Secretion of the immunoregulatory cytokine IL-10 peaked after the fifth i.n. peptide treatment, and although its level subsequently decreased, it remained above those of all other cytokines tested. These results suggest that repeated peptide administration leads to suppression of the Th1-associated cytokines, IL-2 and IFN-γ, produced as an early response to antigen in vivo, while sparing IL-10 production.


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)

Changes in serum cytokine profile over the course of tolerance induction. Tg4 Rag1−/− mice were bled before treatment and after each successive i.n. MBP Ac1-9[4Y] administration. Serum concentrations of IL-2, IL-10, IFN-γ, IL-17, IL-4, and IL-5 were measured by cytometric bead assay. Results show the mean serum cytokine concentration of six to eight mice per treatment group on pooled data from two separate experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig1: Changes in serum cytokine profile over the course of tolerance induction. Tg4 Rag1−/− mice were bled before treatment and after each successive i.n. MBP Ac1-9[4Y] administration. Serum concentrations of IL-2, IL-10, IFN-γ, IL-17, IL-4, and IL-5 were measured by cytometric bead assay. Results show the mean serum cytokine concentration of six to eight mice per treatment group on pooled data from two separate experiments.
Mentions: Peripheral tolerance is induced in the Tg4 TCR transgenic mouse by repeated i.n. administration of antigenic peptide (Burkhart et al., 1999). This results in the generation of IL-10–secreting T reg cells capable of suppressing immune responses in vivo (Sundstedt et al., 2003). To investigate the differentiation pathway of peptide-induced IL-10 T reg cells, we first sought to determine changes in the serum cytokine profile over the course of tolerization in Tg4 Rag1−/− mice. Serum concentrations of IL-2, IFN-γ, IL-17, IL-4, IL-5, and IL-10 were assessed at 2 h after successive i.n. peptide administration (Fig. 1). The 2-h time point represents the peak of cytokine secretion, as determined previously (Sundstedt et al., 2003). As shown in Fig. 1, distinct patterns of serum cytokine levels emerged. The Th1 cytokines IL-2 and IFN-γ followed a similar profile, with the mean serum levels peaking after the second i.n. peptide treatment and decreasing to near background thereafter. IL-17 secretion was delayed relative to the Th1 cytokines with a peak after the fourth i.n. peptide administration. In marked contrast, the Th2 cytokines IL-4 and IL-5 were secreted at only very low levels over the entire course of i.n. peptide treatment. Secretion of the immunoregulatory cytokine IL-10 peaked after the fifth i.n. peptide treatment, and although its level subsequently decreased, it remained above those of all other cytokines tested. These results suggest that repeated peptide administration leads to suppression of the Th1-associated cytokines, IL-2 and IFN-γ, produced as an early response to antigen in vivo, while sparing IL-10 production.

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