Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells’ signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

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DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021309118 ◽

2021 ◽

Vol 118 (21) ◽

pp. e2021309118

Author(s):

Kazuki Sato ◽

Yumi Yamashita-Kanemaru ◽

Fumie Abe ◽

Rikito Murata ◽

Yuho Nakamura-Shinya ◽

...

Keyword(s):

Treg Cell ◽

Intracellular Signaling ◽

Cell Function ◽

Inflammatory Diseases ◽

Mammalian Target Of Rapamycin ◽

Foxp3 Expression ◽

Treg Cells ◽

Cell Dysfunction ◽

Inflammatory Conditions ◽

Treg Cell Function

Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1–mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B–mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.

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Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00599-z ◽

2021 ◽

Author(s):

Marc Permanyer ◽

Berislav Bošnjak ◽

Silke Glage ◽

Michaela Friedrichsen ◽

Stefan Floess ◽

...

Keyword(s):

T Cell ◽

Treg Cell ◽

Cell Function ◽

Interleukin 2 ◽

Foxp3 Expression ◽

Treg Cells ◽

Receptor Expression ◽

Spontaneous Mutant ◽

Cell Pool ◽

And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

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SOCS1 and Regulation of Regulatory T Cells Plasticity

Journal of Immunology Research ◽

10.1155/2014/943149 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Reiko Takahashi ◽

Akihiko Yoshimura

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Molecular Mechanisms ◽

Foxp3 Expression ◽

Negative Regulator ◽

Cytokine Signaling ◽

Cell Integrity ◽

Inflammatory Conditions ◽

A Minor ◽

And Function

Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3+T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.

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Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice

BioMolecular Concepts ◽

10.1515/bmc-2011-0033 ◽

2012 ◽

Vol 3 (3) ◽

pp. 241-253 ◽

Cited By ~ 4

Author(s):

Sabine Hübner ◽

Jan Tuckermann

Keyword(s):

Side Effects ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Pathological Condition ◽

Cell Types ◽

Therapeutic Effects ◽

Gene Promoters ◽

Inflammatory Conditions ◽

Anti Inflammatory ◽

And Function

AbstractGlucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided.

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G Protein-Coupled Receptor 83 Is Dispensable for the Development and Function of Regulatory T Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01075-07 ◽

2007 ◽

Vol 27 (23) ◽

pp. 8065-8072 ◽

Cited By ~ 16

Author(s):

Li-Fan Lu ◽

Marc A. Gavin ◽

Jeffrey P. Rasmussen ◽

Alexander Y. Rudensky

Keyword(s):

T Cells ◽

G Protein ◽

Treg Cell ◽

Cell Biology ◽

Molecular Mechanisms ◽

Foxp3 Expression ◽

Treg Cells ◽

G Protein Coupled Receptor ◽

And Function ◽

G Protein Coupled

ABSTRACT Global analyses of gene expression in regulatory T (Treg) cells, whose development is critically dependent upon the transcription factor Foxp3, have provided many clues as to the molecular mechanisms these cells employ to control immune responses and establish immune tolerance. Through these studies, G protein-coupled receptor 83 (GPR83) was found to be expressed at high levels in Treg-cell populations. However, its function remained unclear. Recently, it has been suggested that GPR83 is involved in the induction of Foxp3 expression in the peripheral nonregulatory Foxp3− CD4 T cells. To examine a role for GPR83 in Treg-cell biology, we generated and characterized GPR83-deficient mice. We have shown that GPR83 abolition does not result in measurable pathology or changes in the numbers or function of Foxp3+ Treg cells. Furthermore, while in vitro analysis suggested a potential involvement of GPR83 in transforming growth factor β-dependent Foxp3 induction, there was no difference in the ability of nonregulatory GPR83-deficient and nondeficient Foxp3− T cells to acquire Foxp3 expression in vivo. Collectively, our results demonstrate that GPR83 is dispensable for Treg-cell development and function.

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Expression and function of Smad7 in autoimmune and inflammatory diseases

Journal of Molecular Medicine ◽

10.1007/s00109-021-02083-1 ◽

2021 ◽

Author(s):

Yiping Hu ◽

Juan He ◽

Lianhua He ◽

Bihua Xu ◽

Qingwen Wang

Keyword(s):

Posttranscriptional Regulation ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Kidney Diseases ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Signaling Mechanism ◽

And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

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Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

Scientific Reports ◽

10.1038/s41598-021-96184-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mei Ding ◽

Rajneesh Malhotra ◽

Tomas Ottosson ◽

Magnus Lundqvist ◽

Aman Mebrahtu ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Foxp3 Expression ◽

Treg Cells ◽

Secreted Proteins ◽

External Stimulation ◽

Marker Proteins ◽

Positive Regulators ◽

Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

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Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1907224116 ◽

2019 ◽

Vol 116 (51) ◽

pp. 25790-25799 ◽

Cited By ~ 5

Author(s):

Sung Woong Jang ◽

Soo Seok Hwang ◽

Hyeong Su Kim ◽

Min Kyung Kim ◽

Woo Ho Lee ◽

...

Keyword(s):

Essential Role ◽

Foxp3 Expression ◽

Treg Cells ◽

Negative Regulator ◽

Delayed Type Hypersensitivity ◽

Type I ◽

Signature Genes ◽

Homeobox Protein ◽

The Stability ◽

And Function

Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis, but the suppressive function of Treg cells can be an obstacle in the treatment of cancer and chronic infectious diseases. Here, we identified the homeobox protein Hhex as a negative regulator of Treg cells. The expression of Hhex was lower in Treg cells than in conventional T (Tconv) cells. Hhex expression was repressed in Treg cells by TGF-β/Smad3 signaling. Retroviral overexpression of Hhex inhibited the differentiation of induced Treg (iTreg) cells and the stability of thymic Treg (tTreg) cells by significantly reducing Foxp3 expression. Moreover, Hhex-overexpressing Treg cells lost their immunosuppressive activity and failed to prevent colitis in a mouse model of inflammatory bowel disease (IBD).Hhexexpression was increased; however,Foxp3expression was decreased in Treg cells in a delayed-type hypersensitivity (DTH) reaction, a type I immune reaction. Hhex directly bound to the promoters ofFoxp3and other Treg signature genes, includingIl2raandCtla4, and repressed their transactivation. The homeodomain and N-terminal repression domain of Hhex were critical for inhibiting Foxp3 and other Treg signature genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3.

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TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909687116 ◽

2019 ◽

Vol 116 (43) ◽

pp. 21666-21672 ◽

Cited By ~ 8

Author(s):

Wen-Yi Tseng ◽

Yi-Shu Huang ◽

Felix Clanchy ◽

Kay McNamee ◽

Dany Perocheau ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

Transcription Factor ◽

Autoimmune Disease ◽

Foxp3 Expression ◽

Treg Cells ◽

Immune Homeostasis ◽

Tnf Receptor ◽

Phenotypic Stability ◽

Inflammatory Conditions

Regulatory T (Treg) cells expressing the transcription factor Foxp3 play an important role in maintaining immune homeostasis. Chronic inflammation is associated with reduced Foxp3 expression, function, and loss of phenotypic stability. Previous studies have established the importance of TNF receptor 2 (TNFR2) in the generation and/or activation of Treg cells. In this study, we assess the importance of TNFR2 in healthy mice and under inflammatory conditions. Our findings reveal that, in health, TNFR2 is important not only for the generation of Treg cells, but also for regulating their functional activity. We also show that TNFR2 maintains Foxp3 expression in Treg cells by restricting DNA methylation at the Foxp3 promoter. In inflammation, loss of TNFR2 results in increased severity and chronicity of experimental arthritis, reduced total numbers of Treg cells, reduced accumulation of Treg cells in inflamed joints, and loss of inhibitory activity. In addition, we demonstrate that, under inflammatory conditions, loss of TNFR2 causes Treg cells to adopt a proinflammatory Th17-like phenotype. It was concluded that TNFR2 signaling is required to enable Treg cells to promote resolution of inflammation and prevent them from undergoing dedifferentiation. Consequently, TNFR2-specific agonists or TNF1-specific antagonists may be useful in the treatment of autoimmune disease.

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Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

Molecular Biology of the Cell ◽

10.1091/mbc.e14-08-1323 ◽

2015 ◽

Vol 26 (15) ◽

pp. 2845-2857 ◽

Cited By ~ 51

Author(s):

Magdalena Walecki ◽

Florian Eisel ◽

Jörg Klug ◽

Nelli Baal ◽

Agnieszka Paradowska-Dogan ◽

...

Keyword(s):

T Cells ◽

Androgen Receptor ◽

Treg Cell ◽

Foxp3 Expression ◽

Treg Cells ◽

Strong Increase ◽

Histone H4 ◽

And Function

CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.

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