Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?

Huehn, Jochen; Polansky, Julia K.; Hamann, Alf

doi:10.1038/nri2474

Cited by 469 publications

(446 citation statements)

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“…Transcription factors can help to alter the epigenetic state of cytokine genes by binding to DNA and preventing remethylation (that is, passive demethylation). 21,45,46 We model this by allowing transcription factors to occupy nonmethylated CpG islets on the cytokine gene, thereby preventing methylation (for instance, through preventing DNMTs from binding to DNA), and promoting a shift to a nonmethylated state. In summary, our model describes a master transcription factor that promotes its own expression, upregulates cytokine expression and inhibits methylation of the cytokine locus.…”

Section: Box 1 Positive Feedback Creates Attractorsmentioning

confidence: 99%

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Ham

Boer

2012

Immunol Cell Biol

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Following activation by antigen, helper T cells differentiate into one of many effector phenotypes. Formulating mechanistic mathematical models combining regulatory networks at the transcriptional, translational and epigenetic level, we study how individual helper T cells may adopt their different phenotypes. For each cytokine phenotype, for example, T helper type 1 (Th1) and type 2 (Th2) cells, we find that the intracellular molecular network allows a cell to adopt one of the three states, which we interpret as naive, active and memory states. Cell division markedly speeds up the differentiation into a particular memory state because of DNA demythelation. In a memory state, cells readily resume production of the same cytokine they produced before. Using stochastic models we show that helper T-cell plasticity (that is, the ability to switch phenotype) is low during clonal expansion. Although most memory cells rapidly secrete the original cytokine upon restimulation, some adopt another phenotype and produce different cytokines, allowing for considerable diversity in the phenotypes that are adopted during a memory response. In summary, we show that helper T-cell division expedites cell differentiation by increasing DNA demethylation. We also show that plasticity is low during the clonal expansion phase, but that helper T cells may adopt alternative phenotypes during a memory response. Keywords: epigenetic regulation; helper T-cell phenotypes; mathematical modelling; transcriptional regulation For more than a century, biologists have studied the mechanisms that enable cells to encode genetic information, and how this information is passed on to the cell's progeny. 1 Besides the genetic DNA code of a cell that is replicated faithfully upon every cell division and therefore virtually identical in every cell within an individual, 2 additional 'epigenetic' information fixes differential cell development by prompting daughter cells to express a similar set of genes as their mother cell. 3 This facilitates and thus preserves the differentiation process that the mother cell and its ancestors have undergone as part of cellular diversification within an organism.A variety of biological systems have now been studied using highthroughput technologies, which provide data that allow a better understanding of information processing within a cell. [4][5][6][7] The availability of quantitative data and the apparent complexity of cellular regulatory networks have led to a data-driven mathematical modelling approach that is usually referred to as computational or systems biology. Mathematical models have revealed nonlinearity in genetic networks that allow cells to switch between states. Examples are the Lac operon 8 and cells of the haematopoietic lineage. [9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models. [13][14][15] At the molecular level these mathematical models describe quite different genetic and epigenetic systems. Mathematically they share im...

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Section: Box 1 Positive Feedback Creates Attractorsmentioning

confidence: 99%

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Ham

Boer

2012

Immunol Cell Biol

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“…Moreover, TGF-b-induced iTreg exhibit unstable Foxp3 expression, while the majority (although not all) of natural Foxp3 1 T cells exhibit stable Foxp3 expression [8,9]. Importantly, the stable Foxp3 expression in natural Treg is associated with chromatin remodeling of the Foxp3 locus, particularly complete demethylation of one of the evolutionary conserved non-coding sequence (CNS) elements termed the Treg-specific demethylation region (TSDR) [8]. These findings collectively suggest that there are multiple, presumably redundant, pathways leading to Foxp3 induction and that Foxp3 expression itself is not sufficient to commit Treg precursors to the Treg lineage and to imprint them with permanent Foxp3 expression and Treg function.…”

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confidence: 99%

“…In addition, it has also become evident that Foxp3 1 Treg can also be generated from peripheral naive CD4 1 T cells upon ''tolerogenic'' antigen presentation in vivo or activation in the presence of TGF-b in vitro (so-called induced iTreg) [6]. Although thymusderived Treg and peripherally generated Treg share some functional and phenotypic characteristics, it is becoming clear that they are different in many aspects, particularly in terms of gene expression, phenotypic stability and mechanistic requirements for differentiation [5][6][7][8]. Although TCR signals are central for both thymic and peripheral Treg induction, ''quality'' of the TCR signals appears different.…”

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confidence: 99%

“…While thymic Treg differentiation requires high-affinity/avidity TCR interactions together with costimulatory signals through CD28, peripheral Treg induction depends on suboptimal TCR stimulation in the absence of CD28 co-stimulation and on TGF-b [5,6]. Moreover, TGF-b-induced iTreg exhibit unstable Foxp3 expression, while the majority (although not all) of natural Foxp3 1 T cells exhibit stable Foxp3 expression [8,9]. Importantly, the stable Foxp3 expression in natural Treg is associated with chromatin remodeling of the Foxp3 locus, particularly complete demethylation of one of the evolutionary conserved non-coding sequence (CNS) elements termed the Treg-specific demethylation region (TSDR) [8].…”

mentioning

confidence: 99%

“…Thus, Treg lineage is likely determined by a higher-order regulatory process that operates upstream of Foxp3, which ensures stable and high-level Foxp3 expression (see [7,10] for more detailed discussion). Elucidation of the molecular nature of such a regulatory system, more specifically the one that opens and remodels the Foxp3 locus, remains a major challenge in the field [8].…”

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confidence: 99%

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c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

Hori

2010

Eur J Immunol

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The transcription factor Foxp3 controls the differentiation and function of Treg, but the molecular mechanisms that regulate Foxp3 transcription remain elusive. In particular, signals and factors that open and remodel the Foxp3 locus and imprint developing Treg with a stable Foxp3 phenotype are largely unknown. Two reports in this issue of the European Journal of Immunology, together with recent reports published elsewhere, demonstrate that a member of the NF-jB family transcription factors, c-Rel, is required for thymic differentiation of Foxp3 1 Treg. Moreover, c-Rel is shown to regulate Foxp3 transcription directly by binding to cis-regulatory elements at the Foxp3 locus upon TCR/CD28 stimulation, including the promoter and the newly identified conserved non-coding DNA sequence harboring a ''permissive'' chromatin status in Treg precursors. These findings collectively suggest that c-Rel may act as a pioneer transcription factor in initiating Foxp3 transcription in Treg precursors in the thymus.

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Immunological Tolerance: Mechanisms

Zouali

2014

Encyclopedia of Life Sciences

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Immunological tolerance refers to a reduction or complete inhibition of the ability of an individual to mount a specific immune response upon immunisation. Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion, clonal anergy, receptor editing, receptor down‐modulation and lymphocyte sequestration. The number of antigen presenting cells, the number and activity of regulatory T cells and regulatory B cells, the nature and amount of antigenic peptides generated and the presence of co‐stimulatory signals in a particular tissue are also important. Depending on the site and the level of antigen expression, different states of peripheral B‐cell and T‐cell tolerance can be reached. In certain situations, they could act in an additive manner. In humans, induction of immunological tolerance is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance. Key Concepts: Tolerance induction is easier in animals with an immature immune system or with a mature immune system that has been compromised by irradiation, drugs or thoracic drug drainage. In general, when a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance. The introduction route is a key variable in tolerance induction, particularly in adult animals, presumably by determining the accessibility of the antigen to professional antigen presenting cells. The tolerant state is not absolute and tolerance is rarely complete. With time, it gradually wanes and eventually disappears, but it can be deliberately terminated by several means. Persistence of the tolerogen in the periphery and its accessibility to the immune system are generally required to maintain tolerance, which continuously inactivates newly emerging T and B cells that develop in lymphoid organs. T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, a process known as negative selection. Similarly, self‐reactive B cells are purged from the functional repertoire during the transition from the pre‐B to mature B‐cell stage in the bone marrow. Anergy is a functionally silent state induced in B cells and T cells, allowing them to persist functionally inactivated in tolerant animals. Receptor editing is a form of receptor processing that markedly alters the variable region genes expressed by B cells and, consequently, changes the specificity of the surface immunoglobulin and maintains B‐cell tolerance to self. Two functional lymphocyte subsets, called regulatory T cells and regulatory B cells, have recently been found to contribute to the maintenance of the fine equilibrium required for immune tolerance. In humans, induction of immunological tolerance in the adult is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.

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Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?

Cited by 469 publications

References 68 publications

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

Immunological Tolerance: Mechanisms

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