Foxp3 Post-translational Modifications and Treg Suppressive Activity

Deng, Guoping; Song, Xiaomin; Fujimoto, Shigeyoshi; Piccirillo, Ciriaco A.; Nagai, Yoshinori; Greene, Mark I.

doi:10.3389/fimmu.2019.02486

Cited by 107 publications

(83 citation statements)

References 167 publications

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“…Treg cells are essential for maintaining peripheral immune tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases by secreting IL-10 [30,31]. Some studies have reported that the function of Treg cells in RA is partially impaired or that Treg cell number is decreased [32].…”

Section: Discussionmentioning

confidence: 99%

High Levels of CD38+ NK Cells Contribute to Immune Imbalance of Th1/Th2 and Th17/Treg in Rheumatoid Arthritis

Wang¹,

Fang²,

Chang³

2020

Preprint

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Background Increased CD38 expression and CD38+ cell proportion as well as their importance had been reported in rheumatoid arthritis (RA).Methods The proportion of lymphocyte subtypes in RA patients and rats with collagen-induced arthritis (CIA) was examined using flow cytometry. CD38+ NK cells, CD38+ NKT cells and CD4+ T cells as well as mononuclear cells (MNCs) depleted of CD38+ cells were isolated from RA synovial fluid using flow cytometry and cocultured in transwell apparatus.Results This study detected a significantly increased CD38+ NK cell proportion and a decreased CD38+ NKT cell proportion in RA peripheral blood and synovial fluid. The CD38+ NK/CD38+ NKT ratio was positively correlated with the disease activity. A similar result was observed in CIA rats. When CD38+ NK cells were cocultured with MNCs, the Treg cell proportion in MNCs and IL-10 level significantly decreased, and Th17 cell proportion and IFN-γ level increased. When the CD38+ NK cells were pretreated with monoclonal anti-CD38 antibody, Treg cell proportion and IL-10 level significantly increased, and the Th17 cell proportion and IFN-γ and IL-6 level decreased. When CD38+ NK cells were cocultured with CD4+ T cells, the Th1/Th2 and Th17/Treg ratios significantly increased, and mTOR signaling was activated in the cells. When the CD38+ NK cells were pretreated with the anti-CD38 antibody, the opposite result was obtained. Coculturing CD38+ NKT cells with MNCs or CD4+T cells showed opposite results. The anti-CD38 antibody also significantly increased TGF-β expression in the CD38+ NK cells.Conclusions Our results suggest that a high CD38+ NK and low CD38+ NKT proportion in RA elevates Th1/Th2 and Th17/Treg ratio to contribute to the pathogenesis.

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Section: Discussionmentioning

confidence: 99%

High Levels of CD38+ NK Cells Contribute to Immune Imbalance of Th1/Th2 and Th17/Treg in Rheumatoid Arthritis

Wang¹,

Fang²,

Chang³

2020

Preprint

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“…Several studies report that the development and function of Treg cells can be regulated by the acetylation status of FOXP3. In addition, hyperacetylation of FOXP3 can prevent the polyubiquitination and proteasomal degradation of FOXP3, leading to an improved stability and transcriptional activity of FOXP3 and GvHD suppression [108][109][110][111][112][113].…”

Section: Effect Of Hdac Inhibitors On Donor T Cell Activation and Difmentioning

confidence: 99%

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Kim

Santhanam²,

Lim

et al. 2020

IJMS

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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“…Additionally, similar to most transcription factors, FoxP3's function can be modulated by post-translational modifications (such as ubiquitination, acetylation, and phosphorylation), which couple extracellular cues to adjustments of transcriptional programmes [for a review see (22,23)].…”

Section: Treg Cells In Health the Foxp3 Transcription Factormentioning

confidence: 99%

One, No One, and One Hundred Thousand: T Regulatory Cells' Multiple Identities in Neuroimmunity

et al. 2019

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As the Nobel laureate Luigi Pirandello wrote in his novels, identities can be evanescent. Although a quarter of a century has passed since regulatory T cells (Treg) were first described, new studies continue to reveal surprising and contradictory features of this lymphocyte subset. Treg cells are the core of the immunological workforce engaged in the restraint of autoimmune or inflammatory reactions, and their characterization has revealed substantial heterogeneity and complexity in the phenotype and gene expression profiles, proving them to be a most versatile and adaptive cell type, as exemplified by their plasticity in fine-tuning immune responses. Defects in Treg function are associated with several autoimmune diseases, including multiple sclerosis, which is caused by an inappropriate immune reaction toward brain components; conversely, the beneficial effects of immunomodulating therapies on disease progression have been shown to partly act upon the biology of these cells. Both in animals and in humans the pool of circulating Treg cells is a mixture of natural (nTregs) and peripherally-induced Treg (pTregs). Particularly in humans, circulating Treg cells can be phenotypically subdivided into different subpopulations, which so far are not well-characterized, particularly in the context of autoimmunity. Recently, Treg cells have been rediscovered as mediators of tissue healing, and have also shown to be involved in organ homeostasis. Moreover, stability of the Treg lineage has recently been addressed by several conflicting reports, and immune-suppressive abilities of these cells have been shown to be dynamically regulated, particularly in inflammatory conditions, adding further levels of complexity to the study of this cell subset. Finally, Treg cells exert their suppressive function through different mechanisms, some of which-such as their ectoenzymatic activityare particularly relevant in CNS autoimmunity. Here, we will review the phenotypically and functionally discernible Treg cell subpopulations in health and in multiple sclerosis, touching also upon the effects on this cell type of immunomodulatory drugs used for the treatment of this disease.

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Foxp3 Post-translational Modifications and Treg Suppressive Activity

Cited by 107 publications

References 167 publications

High Levels of CD38+ NK Cells Contribute to Immune Imbalance of Th1/Th2 and Th17/Treg in Rheumatoid Arthritis

High Levels of CD38+ NK Cells Contribute to Immune Imbalance of Th1/Th2 and Th17/Treg in Rheumatoid Arthritis

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

One, No One, and One Hundred Thousand: T Regulatory Cells' Multiple Identities in Neuroimmunity

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