Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion

Nina Chevalier, Alison N Thorburn, Laurence Macia, Jian Tan, Laurent Juglair, Hideo Yagita, Di Yu, Philip M Hansbro, Charles R Mackay

    Research output: Contribution to journalArticleResearchpeer-review

    10 Citations (Scopus)

    Abstract

    The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
    Original languageEnglish
    Pages (from-to)4845 - 4858
    Number of pages14
    JournalJournal of Immunology
    Volume193
    Issue number10
    DOIs
    Publication statusPublished - 2014

    Cite this

    Chevalier, Nina ; Thorburn, Alison N ; Macia, Laurence ; Tan, Jian ; Juglair, Laurent ; Yagita, Hideo ; Yu, Di ; Hansbro, Philip M ; Mackay, Charles R. / Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion. In: Journal of Immunology. 2014 ; Vol. 193, No. 10. pp. 4845 - 4858.
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    title = "Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion",
    abstract = "The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.",
    author = "Nina Chevalier and Thorburn, {Alison N} and Laurence Macia and Jian Tan and Laurent Juglair and Hideo Yagita and Di Yu and Hansbro, {Philip M} and Mackay, {Charles R}",
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    Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion. / Chevalier, Nina; Thorburn, Alison N; Macia, Laurence; Tan, Jian; Juglair, Laurent; Yagita, Hideo; Yu, Di; Hansbro, Philip M; Mackay, Charles R.

    In: Journal of Immunology, Vol. 193, No. 10, 2014, p. 4845 - 4858.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2-Controlled Regulatory T Cell and Increase of IL-21-Mediated Effector T Cell Expansion

    AU - Chevalier, Nina

    AU - Thorburn, Alison N

    AU - Macia, Laurence

    AU - Tan, Jian

    AU - Juglair, Laurent

    AU - Yagita, Hideo

    AU - Yu, Di

    AU - Hansbro, Philip M

    AU - Mackay, Charles R

    PY - 2014

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    N2 - The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.

    AB - The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.

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    JO - Journal of Immunology

    JF - Journal of Immunology

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