Induced Regulatory T Cells: Their Development, Stability, and Applications

Kanamori, Mitsuhiro; Nakatsukasa, Hiroko; Okada, Masahiro; Lu, Qianjin; Yoshimura, Akihiko

doi:10.1016/j.it.2016.08.012

Cited by 339 publications

(298 citation statements)

References 87 publications

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“…These results are consistent with the reports by other investigators that depletion of T reg cells can result in enhanced immune responses against some infectious agents [52] and that T reg cells can enhance tissue damage and autoimmunity [53–58]. The reports that IL-2 can expand and induce T reg cells in vivo [59] and in vitro [60], are in line with our present study showing that depletion of FoxP3-expressing cells blocked CNS demyelination by HSV-IL-2 and required both IL-2 and viral infection. Thus, IL-2 can modulate effector and T reg cell function in the presence of HSV-1 infection.…”

Section: Discussionsupporting

confidence: 92%

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Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

et al. 2017

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We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

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Section: Discussionsupporting

confidence: 92%

“…Previously, it was shown that IL-2 signaling enhances susceptibility of T cells to apoptosis [61]. In addition, IL-2 impairs T follicular helper (T fh ) cells [62], while enhancing induced T reg (iT reg ) [60]. …”

Section: Discussionmentioning

confidence: 99%

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

et al. 2017

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“…Satb1 ligation on CNS 0 acts as a ‘super‐enhancer’ for foxp3 expression initiation. Illustration based on Kanamori et al . and Iizuka‐Koga et al .…”

Section: Treg Cell Heterogeneity In Stability and Epigeneticsmentioning

confidence: 99%

“…DNA demethylation at this locus is also observed in pTregs, although with slightly reduced levels compared with tT‐regs. In vitro induction of Treg cells (iTreg) in the presence of IL‐2 signals induces demethylation of CNS2, stabilized FOXP3 expression and stable Treg cell phenotype . However, this region is rarely demethylated in iTreg cells in the absence of IL‐2 signalling, which is why FOXP3 expression in this cell subset is highly unstable.…”

Section: Treg Cell Heterogeneity In Stability and Epigeneticsmentioning

confidence: 99%

Human FOXP3⁺ T regulatory cell heterogeneity

et al. 2018

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FOXP3‐expressing CD4+ T regulatory (Treg) cells are instrumental for the maintenance of self‐tolerance. They are also involved in the prevention of allergy, allograft rejection, foetal rejection during pregnancy and of exaggerated immune response towards commensal pathogens in mucosal tissues. They can also prevent immune responses against tumors and promote tumor progression. FOXP3‐expressing Treg cells are not a homogenous population. The different subsets of Treg cells can have different functions or roles in the maintenance of immune homeostasis and can therefore be differentially targeted in the management of autoimmune diseases or in cancer. We discuss here how Treg cell subsets can be differentiated phenotypically, functionally and developmentally in humans.

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“…Among the immune cells involved in the response to tissue injury, recent findings have expanded our understanding of repair mechanisms by demonstrating new and unexpected roles for some immune cells in repairing damaged tissue according to organ-specific cues [2-5]. Forkhead box P3‑expressing (Foxp3 + ) regulatory T (Treg) cells are a heterogeneous population that are specializes in antagonizing overexuberant immune responses and restoring immune homeostasis [6]. Recent studies using transgenic mice specifically ablated Tregs have highlighted their nontraditional function in modulating nonimmunological processes through acting on nonimmune targets [7, 8].…”

Section: Introductionmentioning

confidence: 99%

‘Repair’ Treg Cells in Tissue Injury

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.

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Induced Regulatory T Cells: Their Development, Stability, and Applications

Cited by 339 publications

References 87 publications

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

Human FOXP3⁺ T regulatory cell heterogeneity

‘Repair’ Treg Cells in Tissue Injury

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Induced Regulatory T Cells: Their Development, Stability, and Applications

Cited by 339 publications

References 87 publications

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

Human FOXP3+ T regulatory cell heterogeneity

‘Repair’ Treg Cells in Tissue Injury

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Product

Resources

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Human FOXP3⁺ T regulatory cell heterogeneity