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Foxp3 epigenetics

Karina Oyarce, Mauricio Campos-Mora, Tania Gajardo-Carrasco, Karina Pino-Lagos
Regulatory T cells (Tregs) are critical players of immunological tolerance due to their ability to suppress effector T cell function thereby preventing transplant rejection and autoimmune diseases. During allograft transplantation, increases of both Treg expansion and generation, as well as their stable function, are needed to ensure allograft acceptance; thus, efforts have been made to discover new molecules that enhance Treg-mediated tolerance and to uncover their mechanisms. Recently, vitamin C (VitC), known to regulate T cell maturation and dendritic cell-mediated T cell polarization, has gained attention as a relevant epigenetic remodeler able to enhance and stabilize the expression of the Treg master regulator gene Foxp3, positively affecting the generation of induced Tregs (iTregs)...
2018: Frontiers in Immunology
Anna Nowak, Dominik Lock, Petra Bacher, Thordis Hohnstein, Katrin Vogt, Judith Gottfreund, Pascal Giehr, Julia K Polansky, Birgit Sawitzki, Andrew Kaiser, Jörn Walter, Alexander Scheffold
Regulatory T cells (Tregs) are an attractive therapeutic tool for several different immune pathologies. Therapeutic Treg application often requires prolonged in vitro culture to generate sufficient Treg numbers or to optimize their functionality, e.g., via genetic engineering of their antigen receptors. However, purity of clinical Treg expansion cultures is highly variable, and currently, it is impossible to identify and separate stable Tregs from contaminating effector T cells, either ex vivo or after prior expansion...
2018: Frontiers in Immunology
Kristin Freudenberg, Nadja Lindner, Sebastian Dohnke, Annette I Garbe, Sonja Schallenberg, Karsten Kretschmer
Under physiological conditions, CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 are generated in the thymus [thymus-derived Foxp3+ Treg (tTregs) cells] and extrathymically at peripheral sites [peripherally induced Foxp3+ Treg (pTreg) cell], and both developmental subsets play non-redundant roles in maintaining self-tolerance throughout life. In addition, a variety of experimental in vitro and in vivo modalities can extrathymically elicit a Foxp3+ Treg cell phenotype in peripheral CD4+ Foxp3- T cells, which has attracted much interest as an approach toward cell-based therapy in clinical settings of undesired immune responses...
2018: Frontiers in Immunology
Yufeng Liu, Bo Peng, Shengdi Wu, Nuo Xu
Regulatory T (Treg) cells are a kind of immunosuppression cells, which have been used to treat autoimmune diseases and induce allograft tolerance in clinical trials. While Treg cells based therapy is a promising treatment for kidney diseases and an emerging concept for tolerance induction in renal transplantation, a better understanding of the functions and biology of Treg cells is needed to be able to optimally exploit them. Epigenetics regulation, which refers to potentially heritable alterations in gene expression without underlying changes of the nucleotide sequence, plays an important role in Treg cells induction and maintenance...
February 13, 2018: Current Gene Therapy
Matlock A Jeffries
Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three-dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site-specific DNA binding domain...
February 5, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Manuela Terranova-Barberio, Scott Thomas, Niwa Ali, Nela Pawlowska, Jeenah Park, Gregor Krings, Michael D Rosenblum, Alfredo Budillon, Pamela N Munster
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy...
December 26, 2017: Oncotarget
Yoon Seok Choi, Min Kyung Jung, Jeewon Lee, Seong Jin Choi, Sung Hoon Choi, Hyun Woong Lee, Jong-Joo Lee, Hyung Joon Kim, Sang Hoon Ahn, Dong Hyeon Lee, Won Kim, Su-Hyung Park, Jun R Huh, Hyoung-Pyo Kim, Jun Yong Park, Eui-Cheol Shin
BACKGROUND AND AIMS: CD4+ CD25+ Foxp3+ T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. METHODS: We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea...
March 2018: Gastroenterology
Can Hou, Yanjun Zhong, Zhen Wang, Zhao Ming, Gan Huang, Lin Ouyang, Yijun Li, Qianjin Lu, Zhiguang Zhou
In LADA patients, Tregs are reduced and FOXP3 is downregulated in CD4+ T cells, but the etiology remains unclear. Our study included in 20 LADA patients and 20 healthy control patients. qRT-PCR results showed that STAT3, HDAC3, HDAC5, SIRT1, DNMT1 and DNMT3b mRNAs were significantly upregulated in LADA CD4+ T cells than controls, while FOXP3 mRNA significantly decreased. p-STAT3, STAT3, DNMT1 and DNMT3b expressions were increased demonstrated by western blot. ChIP-PCR suggested that p-STAT3 binds to the Foxp3 promoter, meanwhile, histone H3 acetylation at K9 and K14 of FOXP3 promoter were significantly lower than controls...
December 6, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
David Briere, Niranjan Sudhakar, David M Woods, Jill Hallin, Lars D Engstrom, Ruth Aranda, Harrah Chiang, Andressa L Sodré, Peter Olson, Jeffrey S Weber, James G Christensen
Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells...
November 9, 2017: Cancer Immunology, Immunotherapy: CII
Hyun-Joo Kim, Gil Sun Cha, Ji-Young Joo, Juyoun Lee, Sung-Jo Kim, Jeongae Lee, So Youn Park, Jeomil Choi
Purpose: Beyond the limited scope of non-specific polyclonal regulatory T cell (Treg)-based immunotherapy, which depends largely on serendipity, the present study explored a target Treg subset appropriate for the delivery of a novel epitope spreader Pep19 antigen as part of a sophisticated form of immunotherapy with defined antigen specificity that induces immune tolerance. Methods: Human polyclonal CD4(+)CD25(+)CD127(lo-) Tregs (127-Tregs) and naïve CD4(+)CD25(+)CD45RA(+) Tregs (45RA-Tregs) were isolated and were stimulated with target peptide 19 (Pep19)-pulsed dendritic cells in a tolerogenic milieu followed by ex vivo expansion...
October 2017: Journal of Periodontal & Implant Science
Yohko Kitagawa, Shimon Sakaguchi
Treg cells expressing the transcription factor Foxp3 are essential for immunological tolerance and homeostasis. Recent genome-wide studies have revealed that Foxp3+ natural Treg cells possess a number of unique transcriptional and epigenetic features, which appear to be acquired along the course of Treg cell development and maintained throughout their lifespan. These studies also provide novel insights into how genomic variations contribute to genetic susceptibility to human autoimmune diseases by affecting Treg cell development and function...
December 2017: Current Opinion in Immunology
Roberto Pili, David I Quinn, Hans J Hammers, Paul Monk, Saby George, Tanya B Dorff, Thomas Olencki, Li Shen, Ashley Orillion, Dominick Lamonica, Roberto S Fragomeni, Zsolt Szabo, Alan Hutson, Adrienne Groman, Susan M Perkins, Richard Piekarz, Michael A Carducci
Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Valeria D'Argenio, Valentina Del Monaco, Lorella Paparo, Fatima Domenica Elisa De Palma, Rita Nocerino, Francesca D'Alessio, Feliciano Visconte, Valentina Discepolo, Luigi Del Vecchio, Francesco Salvatore, Roberto Berni Canani
BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We shown that DNA methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggest that also the miRNome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate miRNome in children with CMA and in healthy controls. METHODS: Peripheral blood mononuclear cells were obtained from children aged 4-18 months: 10 CMA patients, 9 CMA patients who outgrew CMA, and 11 healthy controls...
August 30, 2017: Allergy
Tatiana Akimova, Tianyi Zhang, Dmitri Negorev, Sunil Singhal, Jason Stadanlick, Abhishek Rao, Michael Annunziata, Matthew H Levine, Ulf H Beier, Joshua M Diamond, Jason D Christie, Steven M Albelda, Evgeniy B Eruslanov, Wayne W Hancock
Experimental data indicate that FOXP3+ Tregs can markedly curtail host antitumor immune responses, but the properties of human intratumoral Tregs are still largely unknown, in part due to significant methodologic problems. We studied the phenotypic, functional, epigenetic, and transcriptional features of Tregs in 92 patients with non-small-cell lung cancer, comparing the features of Tregs within tumors versus corresponding blood, lung, and lymph node samples. Intratumoral Treg numbers and suppressive function were significantly increased compared with all other sites but did not display a distinctive phenotype by flow cytometry...
August 17, 2017: JCI Insight
Tao Xu, Kelly M Stewart, Xiaohu Wang, Kai Liu, Min Xie, Jae Kyu Ryu, Ke Li, Tianhua Ma, Haixia Wang, Lu Ni, Saiyong Zhu, Nan Cao, Dongwei Zhu, Yu Zhang, Katerina Akassoglou, Chen Dong, Edward M Driggers, Sheng Ding
Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy)acetic acid, that reprograms the differentiation of T helper 17 (TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 cells...
August 10, 2017: Nature
Ricardo C Ferreira, Henry Z Simons, Whitney S Thompson, Daniel B Rainbow, Xin Yang, Antony J Cutler, Joao Oliveira, Xaquin Castro Dopico, Deborah J Smyth, Natalia Savinykh, Meghavi Mashar, Tim J Vyse, David B Dunger, Helen Baxendale, Anita Chandra, Chris Wallace, John A Todd, Linda S Wicker, Marcin L Pekalski
Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3(+) cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3(+) cells within CD127(low)CD25(low) CD4(+) T cells (here defined as CD25(low)FOXP3(+) T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes...
November 2017: Journal of Autoimmunity
Amir Sharabi, Isaac R Kasper, George C Tsokos
Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute to human and murine lupus immunopathology. PP2A expression in SLE is controlled both epigenetically and genetically, and it is increased in patients with SLE, which contributes to decreased IL-2 production, decreased CD3ζ and increased FcRγ expression on the surface of T cells, increased CREMα expression, hypomethylation of genes associated with SLE pathogenesis, and increased IL-17 production. β regulatory subunit of PP2A regulates IL-2 deprivation-induced T cell death and is decreased in SLE patients...
July 21, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Mana Iizuka-Koga, Hiroko Nakatsukasa, Minako Ito, Takashi Akanuma, Qianjin Lu, Akihiko Yoshimura
Regulatory T cells (Tregs) are an essential cell subset for the maintenance of immune homeostasis. Foxp3 (Forkhead box P3) is the Treg master gene which is essential for immune suppressing activity. In addition, Tregs are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory genes. The molecular mechanisms of Treg development and maintenance have been intensively investigated. Tregs are characterized by expression of the transcription factor Foxp3...
July 11, 2017: Journal of Autoimmunity
Eirini Nikolouli, Matthias Hardtke-Wolenski, Martin Hapke, Michael Beckstette, Robert Geffers, Stefan Floess, Elmar Jaeckel, Jochen Huehn
Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs...
2017: Frontiers in Immunology
Wen-Pyng Wu, Yi-Giien Tsai, Tze-Yi Lin, Ming-Ju Wu, Ching-Yuang Lin
BACKGROUND: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4(+) forkhead box P3 (FOXP3)(+) T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3(+)IL-17(+) T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear. METHODS: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model...
July 10, 2017: BMC Nephrology
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