Regulatory T cells in autoimmune disease

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Abstract

In recent years, the understanding of regulatory T cell (Treg cell) biology has expanded considerably. Key observations have challenged the traditional definition of Treg cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of Treg cell instability, Treg cell plasticity and tissue-specific Treg cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of Treg cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.

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Most cited references 65

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T-bet controls regulatory T cell homeostasis and function during type-1 inflammation

Meghan Koch, Glady’s Tucker-Heard, Nikole R. Perdue … (2009)

Several subsets of Foxp3+ regulatory T (Treg) cells work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1-mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type-1 inflammation. Thus, within a subset of CD4+ T cells, the activities of Foxp3 and T-bet are overlaid, resulting in Treg cells with unique homeostatic and migratory properties optimized for suppression of TH1 responses in vivo.

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Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

Xuyu Zhou, Samantha Bailey-Bucktrout, Lukas T. Jeker … (2009)

Regulatory T (Treg) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3+ T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.

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Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.

Ye Zheng, Ashutosh Chaudhry, Arnold Kas … (2009)

In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.

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Author and article information

Journal

Title: Nature Immunology

Abbreviated Title: Nat Immunol

Publisher: Springer Nature

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date (Electronic): June 20 2018

Article

DOI: 10.1038/s41590-018-0120-4

PMC ID: 7882196

PubMed ID: 29925983

SO-VID: fbf2ba0f-abd9-4a46-89e1-cc9f76ffe896

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http://www.springer.com/tdm

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Regulatory T cells in autoimmune disease

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Abstract

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Gamma Delta T cells

Most cited references 65

T-bet controls regulatory T cell homeostasis and function during type-1 inflammation

Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.

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