Cutting Edge: Mechanisms of IL-2–Dependent Maintenance of Functional Regulatory T Cells

Barron, Luke; Dooms, Hans; Hoyer, Katrina K.; Kuswanto, Wilson; Hofmann, Jerry; O’Gorman, William; Abbas, Abul K.

doi:10.4049/jimmunol.0903940

Cited by 195 publications

(177 citation statements)

References 24 publications

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“…These data, together with earlier studies suggesting that vitamin D increases Foxp3 expression in human naïve T-cell cultures [10,28], indicate that vitamin D acts through several different mechanisms to enhance Foxp3 expression. IL-2 plays a central role in the maintenance of a functional Treg cell compartment [29,30]. Interestingly, our data suggest that one mechanism by which 1α25VitD3 may act to maintain Treg cells is via the observed increased expression of the alpha chain of the IL-2 receptor, CD25, and this could be relevant to all of the pathways proposed above.…”

mentioning

confidence: 69%

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4 + T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3 + regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3 + and IL-10 + CD4 + T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3 + and IL-10 + T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3 + Treg cells over their Foxp3 − T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3 + expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4 + Foxp3 + T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10 + and Foxp3 + Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.Keywords: 1α,25-Dihydroxyvitamin D3 r Asthma r Immune regulation r Regulatory T cells Supporting Information available online IntroductionConsiderable interest exists in the therapeutic potential of regulatory T (Treg) cells to treat a range of immune-mediated patholoCorrespondence: Dr. Catherine M. Hawrylowicz e-mail: catherine.hawrylowicz@kcl.ac.uk gies in humans. This is partly based on evidence obtained from animal models of human disease demonstrating the capacity of Treg cells to control transplant rejection, and to successfully treat autoimmune and allergic disease [1]. Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10 + and Foxp3 + T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4 + T-cell populations, r...

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confidence: 69%

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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“…Several studies have focused on two sets of signals-interleukin-2 (IL-2) and antigen itself [60,61]. Thus, IL-2 is required for the survival of Treg and for maintaining their functional activity by promoting expression of FOXP3 and mediators of suppression, particularly CTLA-4 [62]. Answers to environmental antigens may provide enough IL-2 to maintain a Treg cell repertoire in healthy individuals.…”

Section: Treg Functionsmentioning

confidence: 99%

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

Torres¹,

López-Casado²,

León³

et al. 2017

Physiology and Pathology of Immunology

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The immune system is responsible for the defense of the organism. It controls what is introduced into it and identifies it as self from non-self. The defensive mechanisms activated by the immune system are directed against pathological microbes and toxic or allergenic proteins, and it must avoid responses that produce excessive damage of self-tissues, inducing tolerance to avoid autoimmunity and other immunopathologies. Regulatory Tcells play an essential role in these active processes, using several distinct suppressive mechanisms. The immune dysregulatory diseases result from defects affecting regulatory T cell development and/or function, including the impact of essential genes mutations for Tregulatory cell functions and the associated autoimmune syndromes.

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“…Cytokines-IL-2 foremost-are thought to be the main controllers of Treg proportions and numbers (15)(16)(17)(18)(19)(20)(21)(22), although the relative importance of these controllers varies with location and subphenotype [e.g., the alarmin IL-33 has a more profound role in tissue Tregs (21)(22)(23)]. Perhaps surprisingly, in light of this apparently tight control, there is a wide range of variation in Treg proportions, with several studies having observed up to fourfold variation in the blood of healthy humans (e.g., refs.…”

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confidence: 99%

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Dépis

Kwon

Mathis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.Treg homeostasis | FoxP3 stability | immunoregulation | inbred mice

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Cutting Edge: Mechanisms of IL-2–Dependent Maintenance of Functional Regulatory T Cells

Abstract: Material

Cited by 195 publications

References 24 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

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Cutting Edge: Mechanisms of IL-2–Dependent Maintenance of Functional Regulatory T Cells

Abstract: Material

Cited by 195 publications

References 24 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

Unstable FoxP3 + T regulatory cells in NZW mice

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

Unstable FoxP3 ⁺ T regulatory cells in NZW mice