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Foxp3 epigenetics

Ye Shu, Qinghua Hu, Hai Long, Christopher Chang, Qianjin Lu, Rong Xiao
Autoimmune diseases are characterized by aberrant immune responses against healthy cells and tissues. However, the exact mechanisms underlying the development of these conditions remain unknown. CD4+CD25+ regulatory T cells (Tregs) are a subset of mature T cells which have an important role in maintaining immune homeostasis and preventing autoimmune diseases. Forkhead box p3 (Foxp3), a member of the fork head transcription factor family, is recognized as a marker of CD4+CD25+ Tregs. The decreased number and/or function of CD4+CD25+ Tregs in peripheral blood and related tissues has been demonstrated in systemic lupus erythematosus, systemic sclerosis, and other autoimmune diseases, which are at least partially regulated by epigenetic mechanisms...
September 29, 2016: Clinical Reviews in Allergy & Immunology
Kang Li, Xi Zhang, Li Yang, Xin-Xing Wang, De-Hua Yang, Guo-Qing Cao, Shuai Li, Yong-Zhong Mao, Shao-Tao Tang
Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. Various cells types have been reported to participate in the pro-inflammatory response, including Th1, Th2, Th17, CD8(+) T cells, or NK cells. The suppressive Treg cells, on the contrary, were not functioning properly. The underlying mechanism is largely unknown. Focusing on why the suppressive function of Treg was impaired, we found out methylation status of CpG islands within the Foxp3 promotor of Tregs in BA patients and murine models were both increased...
September 22, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Tarmo Äijö, Xiaojing Yue, Anjana Rao, Harri Lähdesmäki
MOTIVATION: 5-methylcytosine (5mC) is a widely studied epigenetic modification of DNA. The ten-eleven translocation (TET) dioxygenases oxidize 5mC into oxidized methylcytosines (oxi-mCs): 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). DNA methylation modifications have multiple functions. For example, 5mC is shown to be associated with diseases and oxi-mC species are reported to have a role in active DNA demethylation through 5mC oxidation and DNA repair, among others, but the detailed mechanisms are poorly understood...
September 1, 2016: Bioinformatics
Lorella Paparo, Rita Nocerino, Linda Cosenza, Rosita Aitoro, Valeria D'Argenio, Valentina Del Monaco, Carmen Di Scala, Antonio Amoroso, Margherita Di Costanzo, Francesco Salvatore, Roberto Berni Canani
BACKGROUND: DNA methylation of the Th1 and Th2 cytokine genes is altered during cow's milk allergy (CMA). Forkhead box transcription factor 3 (FoxP3) is essential for the development and function of regulatory T cells (Tregs) and is involved in oral tolerance acquisition. We assessed whether tolerance acquisition in children with IgE-mediated CMA is associated with DNA demethylation of the Treg-specific demethylated region (TSDR) of FoxP3. RESULTS: Forty children (aged 3-18 months) were enrolled: 10 children with active IgE-mediated CMA (group 1), 10 children who outgrew CMA after dietary treatment with an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (group 2), 10 children who outgrew CMA after treatment with other formulas (group 3), and 10 healthy controls (group 4)...
2016: Clinical Epigenetics
Sebastian Dietmar Barth, Rudolf Kaaks, Theron Johnson, Verena Katzke, Katharina Gellhaus, Janika Josephin Schulze, Sven Olek, Tilman Kühn
BACKGROUND: Experimental and clinical evidence indicate that inflammatory processes in atherogenesis and the development of cardiovascular complications are promoted by a loss of regulatory T cell (Treg)-mediated immunological tolerance to plaque antigens. Yet, the association between alterations of systemic Treg frequency and cardiovascular disease incidence remains uncertain. METHODS: A nested case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg, comprising a random subcohort (n=778) and primary cases of myocardial infarction (MI, n=276) and ischemic stroke (n=151)...
September 2016: EBioMedicine
Xiang Li, Bing Xiao, Xing-Shu Chen
Multiple sclerosis (MS) is a neurological and chronic inflammatory disease that is mediated by demyelination and axonal degeneration in the central nervous system (CNS). Studies have shown that immune system components such as CD4+, CD8+, CD44+ T cells, B lymphatic cells, and inflammatory cytokines play a critical role in inflammatory processes and myelin damage associated with MS. Nevertheless, the pathogenesis of MS remains poorly defined. DNA methylation, a significant epigenetic modification, is reported to be extensively involved in MS pathogenesis through the regulation of gene expression...
June 17, 2016: Molecular Neurobiology
Bodo C Melnik, Swen Malte John, Pedro Carrera-Bastos, Gerd Schmitz
BACKGROUND: Breastfeeding has protective effects for the development of allergies and atopy. Recent evidence underlines that consumption of unboiled farm milk in early life is a key factor preventing the development of atopic diseases. Farm milk intake has been associated with increased demethylation of FOXP3 and increased numbers of regulatory T cells (Tregs). Thus, the questions arose which components of farm milk control the differentiation and function of Tregs, critical T cell subsets that promote tolerance induction and inhibit the development of allergy and autoimmunity...
2016: Clinical and Translational Allergy
Robert Hilbrands, Ye Chen, Adrian R Kendal, Elizabeth Adams, Stephen P Cobbold, Herman Waldmann, Duncan Howie
Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity, and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3(+) Treg. Here, we show that both in vitro and in vivo generated antigen-specific Foxp3(+) Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model...
2016: Frontiers in Immunology
Alexis Vandenbon, Viet H Dinh, Norihisa Mikami, Yohko Kitagawa, Shunsuke Teraguchi, Naganari Ohkura, Shimon Sakaguchi
High-throughput gene expression data are one of the primary resources for exploring complex intracellular dynamics in modern biology. The integration of large amounts of public data may allow us to examine general dynamical relationships between regulators and target genes. However, obstacles for such analyses are study-specific biases or batch effects in the original data. Here we present Immuno-Navigator, a batch-corrected gene expression and coexpression database for 24 cell types of the mouse immune system...
April 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Manching Ku, Shih-En Chang, Julio Hernandez, Justin R Abadejos, Mohsen Sabouri-Ghomi, Niklas J Muenchmeier, Anna Schwarz, Anna M Valencia, Oktay Kirak
To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3(+)CD4(+)Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) β-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR β-chain was able to provide stronger TCR signals...
April 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Vita Golubovskaya, Lijun Wu
This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4⁺ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8⁺ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc...
2016: Cancers
Olga Sarmento, Yuning Xiong, Zhifu Sun, Phyllis Svingen, Adebowale Bamidele, Thomas Smyrk, Asha Nair, Saurabh Baheti, Dermot McGovern, Jessica Friton, Konstantinos Papadakis, Gautam Goel, Ramnik Xavier, Raul Urrutia, William Faubion
BACKGROUND: Crohn's disease is a common intestinal inflammatory disorder of uncertain etiology and incomplete treatment options. It is characterized by lesions infiltrated by inflammatory CD4 lymphocytes; yet the mechanism of CD4 mediated pathophysiology is unclear. Through whole genome approaches on clinical cohorts of CD patients, combined with functional in-vivo and in-vitro murine data, we sought to identify and evaluate aberrant transcriptional gene networks in disease-associated CD4 cells...
March 2016: Inflammatory Bowel Diseases
Abigail E Overacre, Dario Aa Vignali
Regulatory T cell (T(reg)) stability has been primarily determined by the maintained expression of the transcription factor Forkhead box P3 (Foxp3). However, T(regs) can exhibit instability while maintaining Foxp3 expression, requiring a re-examination of what defines T(reg) stability. Recent work suggests that the establishment and stability of T(regs) is mediated by a number of mechanisms besides Foxp3 expression, such as epigenetic modifications, Foxo1/3a localization, expression of Eos and signaling via Neuropilin-1...
April 2016: Current Opinion in Immunology
Fabien Dépis, Ho-Keun Kwon, Diane Mathis, Christophe Benoist
Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yayoi Shimazu, Yutaka Shimazu, Masakatsu Hishizawa, Masahide Hamaguchi, Yuya Nagai, Noriko Sugino, Sumie Fujii, Masahiro Kawahara, Norimitsu Kadowaki, Hiroyoshi Nishikawa, Shimon Sakaguchi, Akifumi Takaori-Kondo
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1. Because of its immunosuppressive property and resistance to treatment, patients with ATL have poor prognoses. ATL cells possess the regulatory T cell (Treg) phenotype, such as CD4 and CD25, and usually express forkhead box P3 (FOXP3). However, the mechanisms of FOXP3 expression and its association with Treg-like characteristics in ATL remain unclear. Selective demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene leads to stable FOXP3 expression and defines natural Tregs...
February 2016: Cancer Immunology Research
Enass A Abdel-Hameed, Hong Ji, Mohamed Tarek Shata
Human immunodeficiency virus (HIV), a member of the Retroviridae family, is a positive-sense, enveloped RNA virus. HIV, the causative agent of acquired immunodeficiency syndrome (AIDS) has two major types, HIV-1 and HIV-2 In HIV-infected cells the single stranded viral RNA genome is reverse transcribed and the double-stranded viral DNA integrates into the cellular DNA, forming a provirus. The proviral HIV genome is controlled by the host epigenetic regulatory machinery. Cellular epigenetic regulators control HIV latency and reactivation by affecting the chromatin state in the vicinity of the viral promoter located to the 5' long terminal repeat (LTR) sequence...
2016: Advances in Experimental Medicine and Biology
William Y Yang, Ying Shao, Jahaira Lopez-Pastrana, Jietang Mai, Hong Wang, Xiao-Feng Yang
CD4(+)FOXP3(+) regulatory T cells (Tregs) are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance, controlling acute and chronic inflammation, allergy, autoimmune diseases, and anti-cancer immune responses. Over the past 20 years, significant progress has been made since Tregs were first characterized in 1995. Many concepts and principles regarding Tregs generation, phenotypic features, subsets (tTregs, pTregs, iTregs, and iTreg35), tissue specificity (central Tregs, effector Tregs, and tissue resident Tregs), homeostasis (highly dynamic and apoptotic), regulation of Tregs by receptors for PAMPs and DAMPs, Treg plasticity (re-differentiation to other CD4 T helper cell subsets, Th1, Th2, Tfh and Th17), and epigenetic regulation of Tregs phenotypes and functions have been innovated...
December 2015: Burns and trauma
Noriko Komatsu, Hiroshi Takayanagi
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by inflammation and subsequent bone destruction in multiple joints. In mice, depletion of regulatory T (Treg) cells results in the onset of a variety of autoimmune diseases including arthritis, while replenishment of Treg cells alleviates arthritic symptoms. The importance of Treg cells in RA is supported by the effectiveness of CTLA4-Ig therapy, an increased Treg cell/effector T cell ratio after anti-IL-6R or anti-TNF-α treatment and the identification of CTLA-4 as an RA-associated gene...
2015: Progress in Molecular Biology and Translational Science
Annemarie van Nieuwenhuijze, Adrian Liston
Regulatory T cells (Tregs) are characterized by the expression of the master transcription factor forkhead box P3 (Foxp3). Although Foxp3 expression is widely used as a marker of the Treg lineage, recent data show that the Treg fate is determined by a multifactorial signaling pathway, involving cytokines, nuclear factors, and epigenetic modifications. Foxp3 expression and the Treg phenotype can be acquired by T cells in the periphery, illustrating that the Treg fate is not necessarily conferred during thymic development...
2015: Progress in Molecular Biology and Translational Science
Eva Rosenkranz, Claudia H D Metz, Martina Maywald, Ralf-Dieter Hilgers, Inga Weßels, Tina Senff, Hajo Haase, Maximilian Jäger, Melanie Ott, Richard Aspinall, Birgit Plümäkers, Lothar Rink
SCOPE: Zinc is an essential trace element, regulating immune function. Its deficiency results in immune dysfunction and transplant rejection. In here, a benefit of zinc supplementation for the induction of tolerance was investigated, focusing on the TH 1-dominated allogeneic immune reaction. METHODS AND RESULTS: Allogeneic immune reaction was modeled by mixed lymphocyte culture (MLC). The effect of zinc supplementation was monitored via expression of cytokines and surface lineage markers using ELISA and flow cytometry...
March 2016: Molecular Nutrition & Food Research
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