scholarly journals SOCS1 and Regulation of Regulatory T Cells Plasticity

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
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.

scholarly journals SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

2011 ◽  
Vol 208 (10) ◽  
pp. 2055-2067 ◽  
Author(s):  
Reiko Takahashi ◽  
Shuhei Nishimoto ◽  
Go Muto ◽  
Takashi Sekiya ◽  
Taiga Tamiya ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Cell Integrity ◽  
Cell Functions ◽  
Ifn Γ

Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1−/− Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2−/− mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1−/− Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ−/−Socs1−/− Treg cells, the restriction of IFN-γ–STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ−/−Socs1−/− Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ−/−Socs1+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2−/− mice. In vitro experiments suggested that cytokines produced by Socs1−/− Treg cells and Ifnγ−/−Socs1−/− Treg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in Treg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.

scholarly journals Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

2019 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Autoimmune Response ◽  
Wild Type ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Receptor Component ◽  
And Function

AbstractInterleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

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

2015 ◽  
Vol 112 (25) ◽  
pp. E3246-E3254 ◽  
Author(s):  
Yayi Gao ◽  
Jiayou Tang ◽  
Weiqian Chen ◽  
Qiang Li ◽  
Jia Nie ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Conditions ◽  
Forkhead Box ◽  
Binding Partners ◽  
And Function

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.

scholarly journals The Ets-1 transcription factor controls the development and function of natural regulatory T cells

2010 ◽  
Vol 207 (10) ◽  
pp. 2113-2125 ◽  
Author(s):  
Enguerran Mouly ◽  
Karine Chemin ◽  
Hai Vu Nguyen ◽  
Martine Chopin ◽  
Laurent Mesnard ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Regulatory T Cells ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Regulatory Sequence ◽  
Activated T Cells ◽  
And Function

Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1−/−) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1−/− mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1−/− T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1−/− T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1−/− T reg cells showed decreased in vitro suppression activity and did not protect Rag2−/− hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression.

scholarly journals Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions

2016 ◽  
Vol 14 (6) ◽  
pp. 521-528 ◽  
Author(s):  
Jian Gu ◽  
Xuhao Ni ◽  
Xiongxiong Pan ◽  
Hao Lu ◽  
Yunjie Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Conditions ◽  
And Function

scholarly journals Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3194
Author(s):  
Pierre Stéphan ◽  
Raphaëlle Lautraite ◽  
Allison Voisin ◽  
Yenkel Grinberg-Bleyer
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Treg Cells ◽  
Multiple Strategies ◽  
Cell Transcriptome ◽  
And Function ◽  
Novel Therapeutic

Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

scholarly journals Balancing Inflammation: The Link between Th17 and Regulatory T Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maggie L. Diller ◽  
Ragini R. Kudchadkar ◽  
Keith A. Delman ◽  
David H. Lawson ◽  
Mandy L. Ford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Lineage ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Cell Compartments ◽  
Th17 Cell Differentiation ◽  
And Function

CD4+T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+T cells (Th17 cells) represent a distinct subset of the CD4+T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells(TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 andTREGplasticity and discuss the biologic consequences of their unique relationship.

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

2007 ◽  
Vol 27 (23) ◽  
pp. 8065-8072 ◽  
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.

scholarly journals YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Soo Seok Hwang ◽  
Sung Woong Jang ◽  
Min Kyung Kim ◽  
Lark Kyun Kim ◽  
Bong-Sung Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Foxp3 Expression ◽  
And Function ◽  
Expression And Activity

scholarly journals CRISPR Screen in Regulatory T Cells Reveals Ubiquitination Modulators of Foxp3

2020 ◽  
Author(s):  
Jessica T. Cortez ◽  
Elena Montauti ◽  
Eric Shifrut ◽  
Yusi Zhang ◽  
Oren Shaked ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Regulatory T Cells ◽  
Tumor Immunity ◽  
Screening Method ◽  
Foxp3 Expression ◽  
Negative Regulator ◽  
Multiple Cancer ◽  
Primary Mouse ◽  
Gene Regulatory

AbstractRegulatory T cells (Tregs) are required to control immune responses and maintain homeostasis but are a significant barrier to anti-tumor immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of pro-inflammatory properties2, can promote autoimmunity and/or facilitate more effective tumor immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. Despite improved functional genetic tools that now allow for systematic interrogation, dissection of the gene regulatory programs that modulate Foxp3 expression has not yet been reported. In this study, we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Tregs and applied this technology to perform a targeted loss-of-function screen of ∼490 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We discovered several novel modulators including ubiquitin-specific peptidase 22 (Usp22), Ataxin 7 like 3 (Atxn7l3) and ring finger protein 20 (Rnf20). Members of the deubiquitination module of the SAGA chromatin modifying complex, Usp22 and Atxn7l3, were discovered to be positive regulators that stabilized Foxp3 expression; whereas the screen suggested Rnf20, an E3 ubiquitin ligase, is a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein and created defects in their suppressive function that led to spontaneous autoimmunity but protected against tumor growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Tregs could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Tregs. These results reveal novel modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

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