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Campbell, Andrew J. "The role of FOXP4 and FOXP2 in haematological malignancy." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510935.
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Mendoza, Ezequiel [Verfasser]. "FoxP1, FoxP2 and FoxP4 in the song control system of zebra finches: molecular interactions and relevance for vocal learning / Ezequiel Mendoza." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1026695775/34.
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Kozma, Radoslav. "Inferring demographic history and speciation of grouse using whole genome sequences." Doctoral thesis, Uppsala universitet, Zooekologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-299926.
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From an ecological perspective, knowledge of demographic history is highly valuable because population size fluctuations can be matched to known climatic events, thereby revealing great insight into a species’ reaction to past climate change. This in turn enables us to predict how they might respond to future climate scenarios. Prominently, with the advent of high-throughput sequencing it is now becoming possible to assemble genomes of non-model organisms thereby providing unprecedented resolution to the study of demographic history and speciation. This thesis utilises four species of grouse (Aves, subfamily Tetraoninae) in order to explore the demographic history and speciation within this lineage; the willow grouse, red grouse, rock ptarmigan and the black grouse. I, and my co-authors, begin by reviewing the plethora of methods used to estimate contemporary effective population size (Ne) and demographic history that are available to animal conservation practitioners. We find that their underlying assumptions and necessary input data can bias in their application, and thus we provide a summary of their applicability. I then use the whole genomes of the black grouse, willow grouse and rock ptarmigan to infer their population dynamics within the last million years. I find three dominant periods that shape their demographic history: early Pleistocene cooling (3-0.9 Mya), the mid-Brunhes event (430 kya) and the last glacial period (110-10 kya). I also find strong signals of local population history – recolonization and subdivision events – affecting their demography. In the subsequent study, I explore the grouse dynamics within the last glacial period in more detail by including more distant samples and using ecological modelling to track habitat distribution changes. I further uncover strong signals of local population history, with multiple fringe populations undergoing severe bottlenecks. I also determine that future climate change is expected to drastically constrict the distribution of the studied grouse. Lastly, I use whole genome sequencing to uncover 6 highly differentiated regions, containing 7 genes, hinting at their role in adaptation and speciation in three grouse taxa. I also locate a region of low differentiation, containing the Agouti pigmentation gene, indicating its role in the grouse plumage coloration.
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Goatly, Alison. "FOXP1 abnormalities in lymphoma." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611626.
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Baumann, Katrin [Verfasser]. "DNA-Methylierungsmuster im foxp3 Gen in humanen CD4+ FOXP3-exprimierenden T-Zellen / Katrin Baumann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023494183/34.
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Nishioka, Tomohisa. "CD4[+]CD25[+]Foxp3[+] T cells and CD4[+]CD25[-]Foxp3[+] T cells in aged mice." Kyoto University, 2007. http://hdl.handle.net/2433/135647.
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Tse, Yuen-yu Belinda, and 謝宛余. "Expression of FOXP1 in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193527.
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Objectives: Forkhead box protein P1 (FOXP1) is a transcription factor, and a member of the P-subfamily of forkhead box transcription factor and regulate transcription of a subset of genes that involved in various cellular events. It plays a critical role in regulating cell growth and proliferation, differentiation, embryogenesis, adult tissue homeostasis, and possibly tumorigenesis. Predominant nuclear localisation of FOXP1 protein is commonly expressed at low level in normal tissues and upregulated in proliferative cells. Studies have demonstrated that the loss of FOXP1 expression and cytoplasmic mis-localisation is significantly associated with various malignant cancers, including breast cancer. FOXP1 can act either as a tumor suppressor or as an oncogenic protein in cell-type specific functions. It has been shown to be a co-regulator of estrogen receptor alpha and can modify a specific subset of forkhead box transcription factor class O (FOXO)-target genes. We hypothesise that there is association between FOXP1 expression and patient survival, and explore the potential role of FOXP1 expression as a prognostic marker in breast cancer.
Methods: One hundred and twenty breast cancer samples in tissue microarray blocks were examined for FOXP1 expression by immuno-histochemistry. Nuclear and cytoplasmic FOXP1 expression patterns were analysed with clinico-pathological parameters. Statistical analysis was performed using SPSS software to determine the correlation between FOXP1 expression and clinico-pathological parameters. The correlation between subcellular FOXP1 expression and survival was evaluated by COX regression analysis.
Results: Nuclear or cytoplasmic FOXP1 expression showed no association with clinico-pathological parameters. However, our results showed that there was significant association with estrogen receptor and progesterone receptor when nuclear and cytoplasmic scores were combined as total FOXP1 score (p=0.022 and p=0.028 respectively). In univariate analysis, high nuclear and cytoplasmic FOXP1 expression had no significant correlation with poor survival, while high total FOXP1 expression was associated with poor overall and disease-specific survival (p=0.045). Tumor stage and lymph-node involvement were significantly related to poorer overall and disease-specific survival, while other clinico-pathological parameters did not. In breast cancer with advanced tumor grade and lymph-node involvement, overall and disease-specific survival are significantly associated with high FOXP1 expression (p=0.041 and p=0.015 respectively).
Conclusion: Unlike previous reports, our findings show that increased nuclear and cytoplasmic FOXP1 expression were both observed and high total FOXP1 expression was associated with poorer survival, particularly in cases of advance tumor grade and with lymph node metastases. These finding are supported by a recent report that showed that FOXP1 can up-regulate its own expression by binding to the promoter of FOXP1 and promote cell survival of breast cancer cells by suppressing FOXO-induced apoptosis. It may be possible that FOXP1 expression is up-regulated in a positive feedback loop in breast cancer cells such that there is both increased nuclear transcriptional activity and cytoplasm localisation of FOXP1. Further investigation is necessary to understand the role of FOXP1 in the progression of breast cancer and determine its potential use as a prognostic marker.<br>published_or_final_version<br>Pathology<br>Master<br>Master of Medical Sciences
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Tolosa, Montero Mª Amparo. "Gen FOXP2: Esquizofrenia, alucinaciones auditivas y lenguaje." Doctoral thesis, Universitat de València, 2009. http://hdl.handle.net/10803/9945.
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La presente tesis se ha centrado en la evaluación a través de diferentes aproximaciones de la implicación del gen FOXP2, gen sometido a selección positiva en el linaje humano y relacionado directamente con una alteración de uno de los rasgos más característicos de la especie humana, el lenguaje, en la vulnerabilidad a la esquizofrenia. El estudio de asociación caso-control no ha permitido establecer una implicación consistente entre las variantes estructurales analizadas (SNPs y posibles expansiones de trinucleótidos) con las alucinaciones auditivas como fenotipo alternativo a la esquizofrenia. No obstante, la participación del gen FOXP2 en la vulnerabilidad a las alucinaciones auditivas, como componente referido al lenguaje no puede descartarse por completo, ya que el SNP rs2396753 mostró una tendencia hacia la significación y el SNP rs2253478 mostró diferencias significativas para el ítem de Pobreza del Lenguaje de la Escala Manchester.El análisis de la región promotora nos ha permitido valorar que la regulación de la expresión del gen debe ser más compleja de lo que inicialmente se esperaba. El análisis evolutivo muestra que diferentes tramos de la región promotora analizada han evolucionado diferencialmente, encontrándose una región altamente conservada, que curiosamente no parece contener una elevada concentración de sitios de unión a factores de transcripción, como sería lo esperado dada su posible importancia funcional. Esta secuencia se localiza inmediatamente aguas arriba del potencial promotor extraído de las bases de datos mediante herramientas bioinformáticas. Bajo la hipótesis de su pertenencia al núcleo central del promotor, la evaluación funcional de esta región conservada indica que posiblemente contenga elementos represores de la transcripción, al menos en el tipo celular testado, esto es, células procedentes del pulmón, ya que se obtienen mayores niveles de expresión en su ausencia.Dentro de la hipótesis epigenética de la esquizofrenia se llevó a cabo un análisis de los patrones de metilación en dos fragmentos incluidos en una isla CG adyacente al primer exón, no traducido, del gen en tejidos postmorten de pacientes esquizofrénicos y controles. En primer lugar se obtuvo una clara diferencia en el grado de metilación entre el fragmento analizado localizado aguas arriba del primer exón, con ausencia de metilación respecto al localizado aguas abajo, para el que se obtuvieron patrones específicos de metilación. Comparando el grado de metilación en diferentes áreas cerebrales en pacientes con esquizofrenia y controles, se observó que en la circunvolución del parahipocampo el grado de metilación es mayor que en las otras áreas analizadas y además hay indicios de diferencias entre ambos grupos analizados en ambos hemisferios. Los análisis de expresión encaminados a determinar si el grado de de metilación estaba correlacionado con los niveles de expresión no permitieron llegar a resultados concluyentes al respecto.Otro gen de gran interés en la evolución de la especie humana es el gen HAR1A el cual se caracteriza por incluir una región con evolución acelerada en el linaje humano. Se consideró que un gen de las características del gen HAR1A podría constituir también un buen gen candidato para la esquizofrenia, por lo que se llevó un estudio caso control de las mismas características que el realizado con el gen FOXP2. El hecho de no encontrar diferencias significativas en las frecuencias genotípicas, alélicas o haplotípicas en el estudio de asociación caso-control llevado a cabo con el gen HAR1A indica que no parece estar relacionado con la vulnerabilidad a la esquizofrenia, aunque podría estar relacionado con la susceptibilidad a padecer alucinaciones auditivas dentro del contexto psicótico, al obtenerse diferencias globales en la comparación de haplotipos entre pacientes alucinadores y pacientes sin alucinaciones.<br>This thesis has focused in the study of FOXP2 gene, which is the first gene related to a language disorder and which has been subject to positive selection in human lineage, as candidate gene for schizophrenia through different approaches Case-control study didn't allow establishing a consistent relationship between the analyzed structural variants (SNPs and trinucleotide repetitions) and auditory hallucination as alternative phenotype for schizophrenia. Nevertheless, a role of FOXP2 in vulnerability to schizophrenia through its relationship with language cannot be ruled out since SNP rs2396753 showed a trend to significance and SNP rs2253478 showed significative differences for Poverty of Speech. Analysis of promoter region suggests regulation of the expression of the gene is more complex than it was initially expected.Evolutionary analysis of a 6Kb fragment surrounding first exon of the gene revealed different evolutionary rates in different fragments as well as some potential promoter regions. A highly conserved region was detected upstream of the annotated promoter. In order to determine if this highly conserved region should be included in the promoter core functional analyses were performed. These experiments indicated that this region probably contains repressor elements. Under the epigenetic hypothesis of the origin of schizophrenia an analysis of the methylation patterns of a CpG island adjacent to first untranslated was performed. Differences between upstream and downstream region were detected as well as differences for methylation of parahippocampal gyrus in patients and controls and between hemispheres. Quantification of mRNA levels was conducted in order to correlate methylation and expression levels of the gene, with inconclusive results.As a summary, with our results we cannot rule out a role of FOXP2 in the susceptibility to schizophrenia, although no direct evidence has been obtained.
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Lindmayer, Christian [Verfasser], and Sebastian [Akademischer Betreuer] Grundmann. "Die Rolle des Transkriptionsfaktors FoxP1 beim Blutgefäßwachstum." Freiburg : Universität, 2021. http://d-nb.info/1236846036/34.
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Ramcke, Torben [Verfasser]. "The function of RORγt+Foxp3+ biTregs in glomerulonephritis : Die Rolle von RORγt+Foxp3+ biTregs im Rahmen der Glomerulonephritis / Torben Ramcke". Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2019. http://d-nb.info/1221721011/34.
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Stoppe, Muriel. "Synaptische Plastizität im Kleinhirnkortex von FoxP2-mutanten Mäusen." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-81212.
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Die KE-Familie ist das am ausführlichsten untersuchte Beispiel für eine angeborene spezifische Sprachstörung. Die Sprachstörung in dieser Familie wird durch eine heterozygote Punktmutation im FoxP2-Gen hervorgerufen, die R553H-Mutation. Die betroffenen Mitglieder der Großfamilie haben Defizite beim Erlernen komplexer orofazialer Bewegungsabläufe als Grundlage des fließenden Sprechens und zeigen
Störungen beim Sprachverständnis und beim Schreiben.
Untersuchungen an der KE-Familie und an Knockout-Tieren hatten Hinweise auf eine Beteiligung des Kleinhirns an der Sprachstörung der KE-Familie geliefert. Entsprechend war zu erwarten, dass genauere Kenntnisse über den Einfluss vom FoxP2-Gen auf Entwicklung und Funktion des Kleinhirns helfen könnten, die Funktion von FoxP2 und seine Rolle bezüglich dieser Sprachstörung, aber auch in Hinblick auf die Sprachfähigkeit des Menschen weiter aufzuschlüsseln.
Die Experimente, die der vorliegenden Promotionsarbeit zu Grunde liegen, erforschten erstmals den Einfluss der KE-Mutation im FoxP2-Gen auf synaptischer Ebene durch Untersuchungen am in der Literatur ausführlich beschriebenen erregenden Schaltkreis im Kleinhirnkortex von heterozygoten R552H-Mäusen. Elektrophysiologische Messungen dienten dazu, die Verschaltung der Parallelfasern und Kletterfasern auf die Purkinjezelle auf Veränderungen der Übertragungseigenschaften
zu prüfen. Durch Induktion von Langzeitdepression und Paarpulsbahnung
an der Parallelfaser-Purkinjezell-Synapse sollte die synaptische Plastizität
untersucht werden. Es zeigten sich eine intakte Verschaltung der erregenden Eingänge auf die Purkinjezelle, jedoch Veränderungen der Langzeit- und der Kurzzeitplastizität: Nach Induktion von Langzeitdepression entwickelte sich diese signifikant schneller. Die Paarpulsbahnung war bei kurzen Interstimulusintervallen signifikant
verstärkt. Die Befunde sprechen für einen Einfluss des FoxP2-Gens auf die synaptischen Eigenschaften im Kleinhirnkortex. Die Aufschlüsselung dieses Einflusses und seine Bedeutung für die Sprachstörung der KE-Familie und die Sprachentwicklung beim Menschen ist Gegenstand weiterer Forschung.
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Sather, Blythe Duke. "CD4+ Foxp3+ regulatory T cell homing & homeostasis /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8343.
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Peter, Christian. "mTOR signalling and the regulation of FOXP3 expression." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.600239.
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Regulatory T-cells (Treg) are essential for the establishment of self-tolerance and they can be identified by the expression of FOXP3, the "master" transcription factor for the development of Treg. A number of essential Signals, namely TCR engagement, TGF~, as well as the inhibition of the kinase mTOR, have been shown to be crucial for the induction of FOXP3 in the peripheral immune system. Despite recent progress, the molecular mechanisms for induction of FOXP3 remains elusive due, at least in part, to the lack of a cell line that mimics the behavior of primary CD4+ T-cells. Here we report the isolation of a clone B02 from the mouse lymphoma line EL4 that can be induced to express high levels of FOXP3 in up to 50% of the cells. Pharmacological inhibition of mTOR and EAA depletion synergized with TGF~ in the induction, and led to reduced activity of both mTORCl and mTORC2, which seemed to independently contribute to the enhanced FOXP3 expression. Luciferase reporter assays using Foxp3 promoter and enhancer sequences indicated that the mTOR inhibition-mediated increase in FOXP3 expression resulted primarily from enhanced transcriptional activity. In addition to the enhancement of FOXP3 induction, mTOR inhibition reduced the levels of lL-17A, presumably by SOCS-mediated inactivation of STAT3, which could also have accounted for increased Foxp3 transcription. Although the precise targets of mTOR inhibition involved in the regulation of FOXP3 expression have yet to be identified, both luciferase assays and mass spectrometry-based quantitative phospho-proteomics using SILAC labelled B02 cells, have identified promising candidates. This unique EL4 clone could represent a special resource for investigating the signaling events leading to the induction of FOXP3 as well as events downstream of FOXP3 expression.
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Medvedeva, Vera. "Characterization of Foxp2 functions in the mouse cortex." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066118/document.
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Des mutations du gène Foxp2 constituent le premier exemple connu de cause monogénique de troubles de la parole et du langage. Les individus atteints souffrent de difficultés d’articulation (dyspraxie verbale) mais aussi de perturbations du langage parlé et écrit, ce qui indique la présence d’un trouble cognitif. La séquence et la distribution d’expression de ce gène sont remarquablement conservées parmi les vertébrés.Cette thèse visait principalement à identifier les fonctions du facteur de transcription Foxp2 dans le cortex en caractérisant un modèle murin conditionnel dans lequel ce gène a été spécifiquement inactivé dans les neurones corticaux. Ce modèle murin permet ainsi d’étudier certains aspects des pathologies liées à Foxp2, notamment les aspects de communication et les comportements sociaux. En parallèle, j’ai entrepris, sur un autre modèle murin, des études moléculaires afin d’identifier les gènes perturbés par la réduction de l’expression de Foxp2 dans le cortex. L‘ensemble des résultats présentés suggère que l’inactivation de Foxp2 dans le cortex conduit à des défauts subtils des comportements sociaux sans modification majeure de la morphologie du cortex ou des neurones. Je montre en particulier que les souris mutées présentent des changements de vocalisation ultrasonique lors d’interactions entre mâles et femelles. Par ailleurs, en utilisant un modèle de souris hétérozygote pour une mutation dans Foxp2, j’ai identifié parmi les gènes dérégulés le gène Mint2 déjà impliqué chez l’homme dans l’autisme.En conclusion, ces résultats permettront de mieux comprendre le rôle de Foxp2 au niveau cortical chez les souris pour décrypter les mécanismes moléculaires qui ont été sélectionnés chez l’homme pendant l'évolution de la parole et du langage<br>Genetic disruptions of the forkhead box transcription factor FOXP2 in humans cause a severe autosomal-dominant speech and language disorder. FOXP2 expression pattern and genomic structure are highly conserved in distant vertebrates. We hypothesized that this conservation may allow the use of animal models to identify Foxp2 dependent neuronal circuits and molecular networks involved in social behaviors. Therefore I began characterizing Foxp2 functions in the mouse cortex in conventional heterozygous (Foxp2+/-) and conditional (cortex specific) Foxp2 homozygous mutant mice (Nex-Cre; Foxp2lox/lox). Initial characterization of Nex-Cre; Foxp2lox/lox mice revealed no gross alterations in morphological architecture, postnatal development and basic adult behaviors. However, behavioral profiling of Nex-Cre; Foxp2lox/lox mice demonstrated deficiency in specific social behaviors such as approach behavior towards conspecifics and responses of WT interaction partners. Furthermore, Nex-Cre; Foxp2lox/lox mice showed alterations in specific acoustical parameters of ultrasonic vocalizations (USV), and the type of modulation differed in function of social context. Gene expression profiling of Foxp2-positive cortical pyramidal neurons in Foxp2+/- mice revealed the dysregulation of Mint2, a gene involved in approach behavior in mice and autism spectrum disorder in humans. This result was further validated in cortex-specific Foxp2 mutant mice The results deliver first insights into cortical Foxp2 dependent functions in mouse social behaviors. This provides a rational basis for further mechanistic studies of the ancestral functions of cortical Foxp2 that may have been recruited during speech and language evolution
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Lehnert, Jonathan [Verfasser], and Niklas [Gutachter] Bayersdorf. "Einfluss von Osteopontin auf Foxp3-negative konventionelle und Foxp3-positive regulatorische CD4-positive T-Zellen der Maus / Jonathan Lehnert ; Gutachter: Niklas Bayersdorf." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1204366802/34.
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Ocklenburg, Frank. "Bedeutung des Transkriptionsfaktors Foxp3 für die T-Zell-Funktion." [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976625423.
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Nissen, Jesper Klintø. "Control of regulatory T cell lineage differentiation by Foxp3." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609792.
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Zuber, Julien. "Physiologie et pathologie des cellules régulatrices CD4+CD25+FOXP3+." Paris 6, 2007. http://www.theses.fr/2007PA066178.
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Les cellules T régulatrices CD4+CD25fortFOXP3+ jouent un rôle majeur dans le contrôle de la réponse immune adaptative. Un effort considérable a donc été réalisé pour mieux comprendre leur physiologie et disséquer leur rôle en pathologie. Dans une première partie, nous montrons qu’il existe une hétérogénéité ontogénique, phénotypique et fonctionnelle de la population régulatrice du thymus. Une partie importante des cellules régulatrices CD4+CD25fortFOXP3+ du thymus provient de la périphérie. Elles ont un phénotype activé / mémoire et sont pourvues d’un potentiel suppressif, significativement supérieur à celui des thymocytes régulateurs. La contribution des cellules recirculantes aux compartiments thymiques croît avec l’involution du thymus. Dans une seconde partie, nous caractérisons le premier déficit sévère en cellules T régulatrices CD4+CD25fortCD127faibleFOXP3+ chez une patiente atteinte d’un syndrome polyautoimmun, associé à un déficit immunitaire. Une mutation du gène FOXP3 a été éliminée par séquençage génomique. L’expression transitoire de FOXP3 par les lymphocytes T activés est conservée suggérant que l’expression de la protéine FOXP3 n’est pas intrinsèquement compromise
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Douglass, Stephen Mark. "The roles of FOXP3 and CXCR4 in breast cancer." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2402.
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The X-chromosome linked transcription factor, FOXP3, is expressed by epithelial cells from several organs. In these cells it is considered a potent tumour suppressor directly regulating the expression of many important oncogenes. The chemokine receptor, CXCR4, can also direct a number of processes relevant to the development of breast cancer. These include chemotaxis towards the sole ligand for CXCR4, CXCL12, which is expressed at the most common sites of metastatic spread. This study was designed to define further the role FOXP3 plays in metastatic breast cancer, with a particular focus on its potential to regulate CXCR4. In comparison with normal primary breast epithelial cells, FOXP3 was downregulated at both transcript and protein levels in the breast cancer cell lines, MCF-7 and MDA-MB-231. In the more invasive MDA-MB-231, the remaining FOXP3 was located predominately within the cytoplasm and lacked the natural Δ3 isoform. Following stable FOXP3 overexpression in MDA-MB-231, significant decreases were observed in the expression of ErbB2, SKP2, c-MYC and CXCR4. In contrast, an increase in p21 expression led to inhibition of cell proliferation, with a greater proportion in the G1 phase of the cell cycle suggesting the induction of senescence. Specific knockdown of FOXP3 in normal breast epithelial cells with siRNA significantly increased ErbB2, SKP2, c-MYC and CXCR4, and decreased p21 expression. These cells also showed a significantly increased chemotactic response towards CXCL12, suggesting a role for FOXP3 influencing cell migration. The expression of FOXP3 and CXCR4 in normal breast tissue (n=2), and both lymph node negative (n=7) and lymph node positive (n=9) breast cancer samples was investigated by immunohistochemistry. Both epithelial and cancer cells in all the breast cancer samples showed increased CXCR4 expression in comparison to normal tissue. However, the expression of FOXP3 by epithelial or cancer cells did not appear different between all the samples examined. Results from this study are consistent with FOXP3 functioning as an important tumour suppressor in breast cancer. Indeed, the functions of FOXP3 in breast epithelium can now potentially be extended to include influencing the expression of CXCR4 and response to the pro-metastatic chemokine, CXCL12. Further studies should be directed to investigation of the molecular mechanisms involved in this influence of chemokine responsiveness by FOXP3.
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Givel, Anne-Marie. "Rôles de CXCL12beta dans l'hétérogénéité fibroblastique et l'immunosuppression dans les cancers de l'ovaire." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC222.
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Les cancers épithéliaux de l’ovaire sont la première cause de décès par cancer gynécologique. Dans ce travail, nous nous sommes intéressés aux cancers ovariens séreux de haut grade (HGSOC) et de stade avancé, pour lesquels les options thérapeutiques demeurent limitées. Plusieurs laboratoires, dont le nôtre, ont identifié des groupes moléculaires distincts au sein de ces HGSOC sur la base de données transcriptomiques.Dans toutes ces études, un sous-groupe moléculaire, nommé « fibrose » ou« mésenchymateux », est systématiquement observé et invariablement associé à un pronostic sombre pour les patientes. La signature transcriptomique qui identifie ce groupe de patientes inclue de nombreux gènes impliqués dans le remodelage de la matrice extracellulaire et la composition stromale, suggérant un rôle possible du stroma dans l’agressivité de ce sous-groupe moléculaire particulier d’HGSOC.Par une étude combinant de façon originale l’analyse concomitante de 6 marqueurs de fibroblastes associés au cancer (CAF), nous mettons en évidence pour la première fois l’existence de 4 sous-populations de CAF. De façon intéressante, l’une de ces 4 populations(dite CAF-S1) s’accumule significativement dans le sous-type moléculaire« fibrose/mésenchymateux » des HGSOC. Or, cette population particulière de CAF-S1 présente une activité immunosuppressive, en favorisant non seulement la survie ou l’attraction des lymphocytes T régulateurs, mais également en stimulant leur activation par l’expression du facteur de transcription FOXP3 (Forkhead Box P3). Enfin, nous identifions l’isoforme β de CXCL12 (chimiokine à motif C-X-C ligand 12) comme un acteur majeur de l’identité et de la fonctionnalité de ces CAF-S1 immunosuppresseurs. En effet, CXCL12βs’accumule spécifiquement dans les CAF-S1 et joue un rôle clé dans la fonction immunosuppressive de ces CAF au sein du stroma des HGSOC mésenchymateux.Nos résultats mettent ainsi en évidence un mécanisme expliquant, au moins en partie, le pronostic sombre des patientes atteintes d’HGSOC mésenchymateux. La caractérisation approfondie du stroma de ces tumeurs agressives permet d’envisager de nouvelles stratégies thérapeutiques ciblant à la fois les CAF et les cellules immunitaires dans le but d’améliorer la survie des patientes mésenchymateuses<br>Epithelial ovarian cancers are the first cause of death from gynecologic cancer. We focusedour work on high-grade serous ovarian cancer (HGSOC) patients, for who only very fewtherapeutic options exist. In the past, several laboratories, including ours, have identified -based on transcriptomic data- distinct molecular subgroups amongst HGSOC. Interestingly,among these different molecular subgroups, one of them, referred to as “Fibrosis” or“Mesenchymal” is systematically identified and consistently associated with poor patientprognosis in all studies. Transcriptomic signature that defines this specific molecularsubgroup of HGSOC contains mainly genes involved in extracellular matrix remodeling andstromal composition, suggesting a potential role of stroma and Carcinoma-AssociatedFibroblasts (CAF) in this particular “Fibrosis/Mesenchymal” HGSOC subgroup.By combining various technics studying concomitantly 6 different CAF markers, we identifiedfor the first time 4 different subpopulations of CAF in HGSOC. Interestingly, one of thesesub-populations, referred to as CAF-S1, significantly accumulates in the“Mesenchymal/Fibrosis” subgroup of HGSOC. Importantly, we demonstrated that the CAFS1cellular subpopulation exhibits immunosuppressive activities. Indeed, CAF-S1 fibroblastsnot only by attract regulatory T lymphocytes but also promote their survival and activation(assessed by expression of FOXP3). Finally, we uncovered the specific role of the CXCL12βisoform as an important player of CAF-S1 identity and immunosuppressive functions inmesenchymal HGSOC.All together, these results identify a stromal heterogeneity in HGSOC, which has beenbroadly underestimated until now. Moreover, our work demonstrates the accumulation of aCAF subpopulation with immunosuppressive functions in HGSOC mesenchymal patients thatcould account, at least in part, for their poor survival rate. Deep characterization of thestroma may enable us to define new therapeutic options combining CAF-targeting therapiesand immunotherapies, in order to improve survival of HGSOC mesenchymal patients
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Redpath, Stephen Alexander. "Role of ICOS in Foxp3+ Treg responses induced by parasitic helminths." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7649.
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Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring chronic infections. This immune suppression forms a major barrier to the acquisition of protective Th2 immunity, both in regard to natural infections and potential vaccinations. At the same time, immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and epidemiological links between helminth infections and the amelioration of allergy and autoimmunity diseases indicate that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions. Foxp3+ regulatory T cells (Treg) play central downregulatory roles in controlling reactivity to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during infection. Helminths induce dominant Foxp3+ Treg responses that play key roles in inhibiting protective immunity and alleviating immunopathology, and that can protect against allergic inflammation. Thus, Foxp3+ Tregs are a fundamental mechanism of immune regulation during helminth infections, and an understanding of the mechanisms governing the induction of Foxp3+ Treg responses is of principal importance for the design of both prophylactic helminth treatments and therapies for allergies and autoimmunity. However, the nature of the T cell co-stimulatory signals driving Treg generation during helminth infection is largely unclear. Recent evidence suggests that the inducible costimulator (ICOS) contributes to Treg control of autoimmune inflammation. Further, ICOS expression is upregulated by Foxp3+ Treg during infection with the filarial nematode Litomosoides sigmodontis suggesting ICOS is important for Treg during helminth infection. Therefore, we investigated the role of ICOS in helminth-induced Treg responses. Similar to L. sigmodontis infection, Foxp3+ Treg increased ICOS expression in response to infection with the intestinal nematode Heligmosomoides polygyrus and with the blood trematode Schistosoma mansoni. Functionally, ICOS was required for the optimal expansion of lymphoid Treg numbers during early stage H. polygyrus infection and following the onset of the acute egg phase of S. mansoni infection suggesting common pathways for Treg induction by diverse helminth species. Whilst helminth induced proliferation and activation of Foxp3+ Treg was ICOS independent, ICOS was essential for Treg survival in settings of homeostasis and helminth infection. In contrast to the lymph node, Treg responses in the intestinal lamina propria (LP) of ICOS-/- mice were increased due to expanded natural Treg. Following H. polygyrus infection Foxp3+ Helios- CD4+ T cells preferentially expanded in wild-type (WT) mice but not in ICOS deficient mice suggesting ICOS is required for the expansion of adaptive Treg at the site of intestinal nematode infection. Functionally, ICOS supports Treg, but not effector T cells (Teff), H. polygyrus induced IL- 10 production suggesting ICOS differentially regulates Treg and Teff. At the H. polygyrus infection site, ICOS acted to downregulate CD4+ T cell Th2 cytokine production. Conversely, in the reactive lymph node ICOS signalling promoted Th2 immune responses, possibly by maintaining the pool of IL-4 secreting type 2 follicular helper T cells. Thus, ICOS has different effects on Th2 immunity depending on tissue location. Because Th2 immunity governs expulsion of H. polygyrus parasites, the differences in Th2 responses between lymph node and infection site could explain why ICOS deficiency did not impact worm burden. Protective immunity to long-lived helminth infection can be quenched in the initial days of infection by the action of Treg. Whether Treg expand and suppress protective immunity during S. mansoni larvae lung transit has not been investigated. We found that in contrast to H. polygyrus and L. sigmodontis infection, early S. mansoni infection did not induce a Treg response suggesting other mechanisms are employed for immune subversion. During the acute egg-phase of S. mansoni infection, Foxp3+ Treg protect the host from damaging egg-induced hepatic immunopathology. Despite reduced Foxp3+ Treg responses, ICOS deficiency did not impact egg-induced immunopathology. Thus, ICOS co-stimulation contributes to early expansion and the continued maintenance of Treg during helminth infection, both in the local lymph node and at the infection site. ICOS is required for Treg function during helminth infection by promoting IL-10 production, whilst its contribution to Th2 effector immunity is tissue specific. In addition, ICOS is dispensable for protective immunity and pathology during helminth infection. As ICOS controls both positive and negative immune responses and can have opposing roles depending on tissue location, an understanding of the consequences of these contradictory effects will be important when considering targeting ICOS therapeutically.
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Cavalcanti, Yone Vila Nova. "Avaliação do perfil de produção e expressão de mediadores da resposta imune celular em comunicantes e indivíduos com história de tuberculose pulmonar." Universidade Federal de Pernambuco, 2012. https://repositorio.ufpe.br/handle/123456789/10986.
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Previous issue date: 2012<br>A tuberculose pulmonar é um problema de saúde pública mundial e apresenta alta
incidência no Brasil. Atualmente, o Brasil ocupa o 19º lugar no ranking dos 22 países
que concentram 80% dos casos em todo o mundo. A resposta imune humana contra a
tuberculose é especialmente mediada pelos linfócitos T CD4+. Entretanto, muitos
estudos ainda são necessários para o entendimento exato do papel de cada citocina
no mecanismo de cura da doença. A fim de caracterizar a produção das citocinas
TNF-a, IFN-g, IL-10, o óxido nítrico (NO) e a expressão do marcador Foxp3, células
mononucleares do sangue periférico (PBMC) de contatos intradomiciliares de indivíduo
com tuberculose pulmonar com (CTb) e sem (STb) história prévia de TB foram
estimuladas in vitro com antígeno de Mycobacterium tuberculosis (AgTb) e com o
mitógeno Concanavalina A por 24 e 48 horas. A dosagem das citocinas foi feita por
ELISA de captura e de NO pela quantificação do nitrito (NO2
-). PCR em Tempo Real
foi a técnica utilizada para detectar o mRNA para Foxp3. Em 24 horas de cultivo
celular com antígeno total de M. tuberculosis (CTb = 10.158,38 ± 7.438,38; STb =
15.083,10 ± 9.292,66), observou-se uma produção significativa de TNF-a (0,05) no
grupo STb. Os grupos analisados não apresentaram diferenças na expressão do
mRNA do marcador Foxp3. Foi verificado aumento (p= 0,04) entre IL-10 e Foxp3 e
correlação negativa (p = 0,009) entre NO (aumento) e Foxp3 (diminuição) após 48h de
estímulo com AgTb. Observou-se também no grupo STb em 24 horas de culturas
estimuladas com AgTb um resultado semelhante ao grupo CTb (p = 0,03). Portanto, os
resultados obtidos sugerem que produção de IL-10, IFN-g e de NO indicam que os
indivíduos CTb e STb produziram uma resposta celular específica; porém, sem valores
que possam indicar uma maior ou menor susceptibilidade à doença, e que TNF-a,
possivelmente funciona como um elemento fundamental para a manutenção do estado
de saúde dos comunicantes. A expressão do marcador Foxp3 não está associada
diretamente a uma maior predisposição nos indivíduos com história de tuberculose
pulmonar.
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Hermans, Cecilia. "CCL22, CD8 und FoxP3 als prognostische Marker beim fortgeschrittenen Ovarialkarzinom-." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-163564.
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Lin, Li. "The role of FoxN4 in regulating interneuron specification during development." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32562.
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This study seeks to understand the development of neurons constituting the vertebrate spinal locomotory network, which is responsible for the intrinsic generation of rhythmic motor activities. Interneurons (INs) of the V2 class of ventral spinal INs in chick and mouse embryos are sub-divided into V2a and V2b. The V2 sub-classes are of opposite neurotransmitter phenotypes, with the V2a identified as excitatory glutamatergic INs and the V2b being inhibitory GABAergic INs. Their specification during development has been attributed to expression of the transcription factor Foxn4. However, recent over-expression experiments in the chick gave contradicting results as to whether Foxn4 is sufficient to induce V2b INs and if it is also able to suppress the V2a fate. I utilized the much simpler model of embryonic zebrafish with fewer neurons to validate the role of foxn4. I first characterized the expression of different foxn4 transcripts at different developmental stages in the zebrafish and confirmed the expression of an embryonic specific transcript and found that all transcripts are down-regulated in the adult fish. I also determined the cellular identity of V2b INs in the zebrafish, as double in situ hybridization and immunohistochemistry confirmed these to be GABAergic ventral INs. In an attempt to alter the V2a and V2b populations, I either over-expressed foxn4 mRNA or knocked-down its translation using a translation blocking antisense morpholino oligonucleotide. My results indicated no change in V2a or V2b IN numbers when foxn4 was knocked-down, but there was a switch from V2a to V2b when foxn4 was over-expressed. Future experiments could hopefully address if altered<br>Cette étude a pour but d'étudier le développement neuronal du réseau locomoteur spinal chez les vertébrés responsable de la génération intrinsèque des activités motrices rythmiques. Les interneurones (INs) de la classe V2 de la moelle épinière ventrale des embryons de poussins et de souris sont divisés en groupes V2a et V2b. Les sous-classes V2 ont des phénotypes de neurotransmetteurs opposés, avec les V2a étant identifiés comme étant glutamatergiques et excitateurs tandis que les V2b sont GABAergiques et inhibiteurs. Leur spécification durant le développement a été attribué à l'expression du facteur de transcription Foxn4. Par contre des expériences récentes de sur-expression chez le poussin ont données des résultats contradictoires à savoir si le Foxn4 est suffisant pour induire les INs V2b et aussi pour supprimer la destinée V2a. Je me suis servie du modèle beaucoup plus simple de l'embryon du poisson zébré avec moins de neurones afin de valider le rôle de la foxn4. Dans un premier temps j'ai caractérisé l'expression de différents transcrits à des stages différents du développement chez le poisson zébré. J'ai ainsi confirmé l'expression d'un transcrit embryonnaire spécifique et j'ai trouvé que tous les transcrits sont supprimés chez le poisson adulte. J'ai aussi déterminé l'identité cellulaire des INs V2b chez le poisson zébré par double marquage par hybridisation in situ et par immunocytochimie, ce qui a confirmé que ces INs ventraux sont GABAergiques. Afin d'altérer les populations V2a et V2b j'ai soit surexprimé l'ARNm du foxn4 ou réduit son expression par injection d'un oligonucléotide morpholino antisens a
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Chang, Xing. "X-Linked FOXP3 & OTC in immune tolerance and autoimmunity." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149171466.
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Zuo, Tao. "FOXP3 is a novel X-linked breast cancer suppressor gene." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150079443.
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Kendal, Adrian R. "The role of FOXP3+ regulatory T-cells in transplant tolerance." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558327.
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A major conceptual shift in immunology has been the recent discovery of regulatory T- cells (Treg), of which C04+Foxp3+ cells are already known to be essential to self- tolerance. Their role in transplant tolerance remains unproven due to the absence of a natural cell surface marker by which they can be manipulated in vivo. A transgenic B6.Foxp3hCD2 mouse was created to express an artificial GPI-anchored human C02/ C052 surface fusion protein under the control of the Foxp3 promoter. Monoclonal antibodies directed against the human C02 and human C052 were used in B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ Treg. C04+Foxp3+ cells were found to be crucial for transplant tolerance induced by non-ablative co-receptor and eo- tt stimulatory blockade. In tolerant animals, Foxp3+ Treg are constantly required to suppress effector T-cells still capable of causing tissue damage. Remarkably, tolerated tissue contains T-cells capable of rejecting it, but these are prevented from doing so by therapeutically induced Foxp3+ Treg. Finally, induced Foxp3+ cells sustain tolerance by converting naive T-cells into the next generation of Foxp3+ cells in the periphery, providing one potential mechanism by which infectious tolerance may operate in vivo.
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Evans, Amy E. "Characterisation of Foxp1 in striatal development and the adult brain." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/58414/.
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The aim of the research presented in this Thesis was twofold; firstly to further understand the role of Foxp1 in the development of striatal medium spiny neurons (MSN) and secondly its role the adult brain. Understanding the role of Foxp1 in MSN development may allow more accurate in vitro protocols to be generated for use in directing renewable cell sources for use in cell replacement therapies for diseases such as Huntington’s disease (HD). Additionally, its functional role in MSN development may not be exclusive, and thus have a more generalised role transferable to other neuronal processes. Thus what is learnt about its function can possibly be applied to cell transplantation protocols in general, as well as be useful in the drug discovery field. In mice, the transcription factors (TF) Foxp1 and Mef2c were shown to be significantly up-regulated during peak MNS development (embryonic day (E) E12-16) in a genetic screen carried out in the host lab in 2004. Consequently the majority of work in this thesis was focused on the characterisation of the most significantly up-regulated gene, Foxp1. Experiments initially focused on a Foxp1 knock out (KO) line, both in vitro and following transplantation into the quinolinic acid (QA) lesioned adult mouse brain. Additionally, owing to embryonic lethality at E14, a conditional Foxp1 KO (CKO) line was also developed to study the effects of the loss of Foxp1 in the adult brain with a focus on the loss of Foxp1 from the cortex. Owing to lethality at E9 a Mef2c CKO line was also developed and initial in vitro findings from this line are presented in Appendix 8 of this Thesis. Chapter 3 characterised the wild type (WT) expression pattern of FOXP1 from E10 to P7 through the co-localisation of FOXP1 with the established MSN markers CTIP2 and DARPP-32. In vitro characterisation of cultures generated from striate of Foxp1-/- mice showed a decrease in the number of CTIP2 and DARPP-32 positive cells compared to littermate controls but that there were no differences in the proliferation of these cells between groups. Finally, results from immunohistochemistry on selected striatal KO brain sections suggested that Foxp1 may function downstream of Ascl1 and Gsh2 in striatal development. In Chapter 4 E14 or E12 striatal tissue from all three genotypes was grafted into an adult QA-lesion mouse model. Such experiments allowed striatal neurons from Foxp1-/- mice to survive for much longer periods than was possible in vitro and provided them with the opportunity to make some of their normal connections. Results showed that there were fewer DARPP-32 positive cells in grafts from Foxp1-/-compared to controls, as with in Chapter 3. Moreover, FOXP1 was identified as a novel maker of P-zones in grafts derived from whole ganglionic eminence. Chapter 5 addressed the generation of a Foxp1 CKO mouse model under the control of an hGFAP-Cre line (Foxp1 CKO). Histology showed that FOXP1 was lost from all layers of the cortex, but expression was maintained in the striatum. Mice appeared hyperactive in the home cage compared to littermate controls, and as mutations in FOXP1 have been associated with autism spectrum disorders, of which ADHD falls under, led to directed behavioural analysis targeting the symptoms of ADHD. Analysis revealed Foxp1 CKO mice were significantly hyperactive (activity boxe and open-field data) and inattentive (5 choice serial reaction time task) but had no anxiety problems (elevated plus maze and marble burying task). These symptoms were shown to be reduced following the administration of atomoxetine, a drug prescirbed to patients with ADHD. Results collectively suggested that the Foxp1 CKO line is a new mouse model of ADHD.
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Lalfer, Mélanie. "Propriétés de reconnaissance antigénique des lymphocytes T régulateurs CD4+ FOXP3+." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB109.
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Les lymphocytes T régulateurs CD4+Foxp3+ (Treg) sont indispensables au contrôle des cellules T auto-réactives et au maintien de la tolérance immune en périphérie. Ils sont sélectionnés positivement dans le thymus, possèdent un répertoire TCR extrêmement diversifié suggérant une reconnaissance d’antigènes variés, requièrent une signalisation continue via leur TCR pour maintenir leurs fonctions en périphérie, fonctions qu’ils exercent avec une certaine spécificité de tissu. Ils contrôleraient donc spécifiquement les lymphocytes T auto-réactives en reconnaissant comme eux des antigènes du soi. Mon travail de thèse s’est articulé autour de deux axes visant à revisiter ce paradigme de l’autoréactivité des Treg, un point essentiel qui concerne les propriétés de reconnaissance antigénique de ces cellules. Afin de ne pas biaiser nos résultats avec des TCR artificiels, non issus de Treg, nous avons choisi d’étudier les Treg polyclonaux de souris normales. Dans une première série d’expériences, nous avons pu montrer que l’activation de lymphocytes T auto-réactifs anti-mâle dans une souris mâle conduisait à un remodelage du répertoire TCR des Treg, avec un usage préférentiel des Vβ5 et Vβ12. L’absence d’amplification clonale ainsi que des données récentes de la littérature démontrant l’amplification de sous-populations de Treg par des rétrovirus endogènes au cours de réponses immunitaires chroniques, nous ont conduit à conclure que l’activation de lymphocytes T auto-réactifs pourrait réactiver des rétrovirus endogènes et donc l’expression de super-antigènes capables d’amplifier les Treg portant certains Vβ. Dans le second volet de mon travail de thèse, nous avons caractérisé le niveau d’autoréactivité des Treg in vivo. En procédant à une comparaison systématique avec des Treg ayant des niveaux d’allo-réactivité différents et connus, nous avons montré que, de manière inattendue, les Treg polyclonaux possèdent un niveau étonnamment faible d’autoréactivité. Seule une fraction d’entre eux était capable de recevoir un signal TCR et des expériences de quantification ont révélé que cette fraction de cellules auto-réactives ne devait pas excéder 1% du répertoire total des Treg. L’ensemble de nos résultats suggèrent donc que les Treg sont faiblement réactifs en périphérie et/ou sont dirigés contre des antigènes endogènes rarement représentés<br>No abstract available
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Taguchi, Nanae. "HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression." Kyoto University, 2013. http://hdl.handle.net/2433/180612.
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Allan, Sarah E. "Defining the biological role of FOXP3 in human CD4+ T cells." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/1122.
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The involvement of regulatory T cells (Tregs) in immune homeostasis is now recognized as one of the fundamental mechanisms of immune tolerance. While several different types of Tregs cooperate to establish and maintain immune homeostasis, much current research is focused on defining the characteristics of the CD4⁺CD25⁺ Treg subset, as these cells can mediate dominant, long-lasting and transferable tolerance in many experimental models.
The aim of this research was to characterize the biological role of a protein known as forkhead box P3 (FOXP3) that was initially identified as an essential transcription factor for the development of mouse CD4⁺CD25⁺ Tregs, in human CD4⁺ T cells. Following confirmation that, like mouse Tregs, human Tregs also expressed high levels of FOXP3, several approaches were used to investigate the role of this protein in human CD4⁺ T cells. 1) Characterization of endogenous FOXP3 expression in CD4⁺ T cell subsets revealed that this protein is not a Treg-specific marker as was previously thought. Instead, low-level and transient expression was found to be typical of highly activated non-regulatory effector T cells. 2) To generate large numbers of Tregs suitable for cellular therapy, the capacity of ectopic FOXP3 expression to drive Treg generation in vitro was explored. It was found that high and constitutive expression mediated by a lentiviral vector, but not fluctuating expression driven by a retroviral vector, was sufficient to generate suppressive cells. Over-expression strategies were also used to characterize a novel splice isoform unique to human cells, FOXP3Δ2 (FOXP3b). 3) To further probe the requirements of FOXP3 to induce suppressor function, a system for conditionally-active FOXP3 ectopic expression was developed. These studies established that FOXP3 acts a quantitative regulator rather than a “master switch” for Tregs, and that there is a temporal component to its capacity to direct Treg phenotype and function.
In summary, this research has significantly expanded the understanding of the biological function of FOXP3 in human CD4⁺ T cells. Based on the potential of these cells to be manipulated for therapy, this work contributes to the field of immunology on both academic and clinical research fronts.
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Butz, Martin Benedikt. "Erhöhte Anzahl von CD25⁺FOXP3⁺ regulatorischen T-Zellen im oralen Plattenepithelkarzinom /." Regensburg, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254407.
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Fontenot, Jason David. "The role of Foxp3 in CD4⁺ T cell development and function /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8336.
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Holmes, Derek Allan Su Lishan. "Modulation of HIV-1 replication and T cell activation by FoxP3." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1598.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.<br>Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology." Discipline: Microbiology and Immunology; Department/School: Medicine.
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Freyer, Jennifer Sandra Silvia. "Regulation und funktionelle Rolle des murinen Transkriptionsfaktors Foxp3 in T-Zellen." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15841.
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In dieser Arbeit wurde die funktionelle Rolle und Regulation des murinen Transkriptionsfaktor Foxp3 untersucht. Der erste wesentliche Teil zur Analyse der funktionellen Rolle war dabei die Erzeugung einer BAC- transgenen Maus. Hierfür wurde ein Zielgenvektor mit der kodierenden Region des eYFPs und einer dualen Selektionskassette sowie die Methode des ET- Klonierens verwendet. Leider war die homologe Rekombination des Zielgenvektors in den BAC nicht erfolgreich. Es kam zu einer ungeklärten Rekombination mit Fremd- DNS. Die Erzeugung der transgenen Maus wurde nach diesem Ergebnis eingestellt, und es wurde mit einer von unserem Kooperationspartner zur Verfügung gestellten BAC- transgenen Maus weitergearbeitet. Diese Maus, die DEREG- Maus, wurde nach dem gleichen Prinzip erstellt, wie die in dieser Arbeit gestartete transgene Maus, an Stelle des eYFPs trägt die DEREG- Maus die kodierenden Region des GFPs und des Diphtheria- Toxin- Rezeptors. Mit dieser Maus wurden erste Analysen zur Überprüfung der transgenen Maus unternommen. Es wurde die Koexpression von GFP und Foxp3, sowie die Depletion der Foxp3+ T- Zellen mittels Diphtheria- Toxin analysiert. Als nächstes wurde die funktionelle Rolle des Transkriptionsfaktors Foxp3 analysiert. Als einer der ersten Schritte wurde die Stabilität von Foxp3 in vivo überprüft und gezeigt, dass T- Zellen, die das Foxp3- Protein exprimieren, bis zu 14 Tage in vivo stabil sind. Weiterhin wurde die Stabilität der Foxp3- Expression in in vitro Kulturen nach Induktion durch TGF-beta untersucht. Die induzierten Tregs zeigten keine stabile Foxp3- Expression und auch bei der Methylierungsanalyse der TSDR zeigten diese T- Zellen nicht das für ex vivo isolierte Foxp3+ T- Zellen beschriebene Methylierungsmuster. Die Stabilität scheint mit der Demethylierung der TSDR zu korrelieren. Die induzierten Tregs zeigten neben dem nicht stabilen Foxp3- Phänotyp auch eine von der Foxp3- Expression abhängige Suppression von naiven Zellen im in vitro Proliferations- Test. Im dritten Teil der Arbeit wurde die Struktur und Regulation des Transkriptionsfaktors Foxp3 untersucht. Der Lokus wurde auf konservierte Regionen im Vergleich zu den Spezies Maus, Mensch, Ratte, Huhn, Schimpanse, Hund und Frosch untersucht. Die in Floess*, Freyer* et al. (63) gefundenen Region TSDR enthält einen hochkonservierten Bereich. Die Region wurde auf mögliche Transkriptionsfaktor- Bindungsstellen hin analysiert, und ebenfalls wurden in diesem Bereich Histon- Modifikationen für die Acetylierung der Histone H3 und H4, sowie Tri- Methylierung des Lysin4 des Histons H3 gefunden. Die TSDR wurde in Luciferase- Tests auf ihre transkriptionelle Aktivität hin getestet und zeigte einem Enhancer ähnliche unterstützende Aktivität. Die Methylierung der TSDR in den Luciferase- Tests führte zu einer Reduktion der transkriptionellen Aktivität. Deletionsmutanten der TSDR konnten den Bereich für die transkriptionelle Aktivität weiter einschränken und zeigten ein 275pb großes Fragment auf, in welchem viele interessante, mögliche Transkriptionsfaktor- Bindungsstellen und auch die größte Anzahl der differentiell methylierten CpG- Motive liegen.<br>The aim of the study was to analyze the function and regulation of the transcription factor Foxp3. In a first step we designed a BAC-transgenic mouse with eYFP under the control of the Foxp3 promoter. For creating these mice we use the ET- cloning method. The step of homologous recombination of the target vector into the BAC failed. Because of that, we decided to work in cooperation with the group of Tim Sparwasser from Munich and their BAC- transgenic mouse called DEREG- mouse. This mouse expresses the coding region of eGFP fused to the diphtheria- toxin- receptor under the control of the Foxp3 promoter. Therefore Foxp3+ T cells can be easily detected by eGFP expression and can even be depleted by diphtheria- toxin- application. We confirmed the co- expression of Foxp3 and eGFP and furthermore tested the functionality of the depletion- process of Foxp3+ T cells by treatment with diphtheria- toxin. In a second study, we analyzed the stability of Foxp3 expressing cells in vivo. Therefore we transferred Foxp3+ T cells in syngenic mice and analyzed these cells after 14 days for their Foxp3- expression. Furthermore, we tested the induction of Foxp3 expression through TGF-beta and the suppressive activity of these cells. We also analyzed those cells for their methylation pattern, comparing cells, which showed an induction of Foxp3- expression after one week of culture with TGF-beta to cells, which received TGF-beta for one week and were then restimulated in the absence of TGF-beta. The stability of Foxp3 expression seems to correlate with the demethylated state of the TSDR (Treg Specific Demethylated Region). To get a closer look on the region called TSDR in the murine foxp3 locus, we decided to analyze this region under different aspects. First, we checked for putative binding sites of transcription factors by database analysis of the TSDR. We also analysed histon modifications, such as acetylation of histon H3 and H4 and tri- methylation of lysine 4 at histon3, in this region. Presence of these modifications hinted an epigenetic regulation of Foxp3 involving the TSDR. In a last step, the transcriptional activity of TSDR was tested to delineate whether the TSDR serves as an alternative promoter or acts as a regulative element like an enhancer. Luciferase assays showed that TSDR is a regulative enhancer element, which loses transcriptional activity when methylated. Deletion mutants determined the most important fragment of the TSDR.
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Kaur, Gurman. "Functional characterisation of Foxp3 splice variants in human regulatory T cells." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611427.
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Ribot, Julie. "Etude du développement thymique des lymphocytes t régulateurs CD4+ CD25+ Foxp3+." Toulouse 3, 2006. http://www.theses.fr/2006TOU30221.
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Les lymphocytes T régulateurs (LTreg) et conventionnels (LTconv) sont sélectionnés dans le thymus à partir de précurseurs générés aléatoirement. Leur répertoire est très différent : contrairement à sa contrepartie conventionelle, la population régulatrice est enrichie en cellules autospécifiques. Afin d'expliquer ces différences de répertoire, nous avons cherché à mettre en évidence des différences dans la sélection thymique de ces populations. Nous avons d'abord montré que des ligands agonistes naturellement exprimés par les cellules épithéliales thymiques (TEC) favorisent la sélection positive des LTreg, alors qu'ils induisent partiellement la délétion des LTconv. Nous avons ensuite complété ces analyses dans des souris transgéniques pour un ligand unique, dont l'expression est restreinte aux TEC du cortex. Le répertoire des LTreg générés dans ces souris est enrichi en cellules spécifiques pour le ligand unique, contrairement à celui des LTconv. Dans ce modèle, alors que les précurseurs de LTreg spécifiques du ligand sont sélectionnés positivement, ceux des LT conventionnels sont partiellement sélectionnés négativement.
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Händel, Norman. "Die Rolle von Interleukin-2 für die Interaktion von Foxp3+ regulatorischen T-Zellen mit Effektorzellen im Darm." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-67596.
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Natürlich vorkommende regulatorische T-Zellen spielen eine entscheidende Rolle für die intestinale Immunhomöostase und Limitierung von (Auto)-Immunität. Sie exprimieren den Transkriptionsfaktor Foxp3 und an der Oberfläche die α-Kette des IL-2 Rezeptors (CD25). Im Tiermodell verhindern regulatorische T-Zellen Autoimmunopathien, Transplantatabstoßungen und entzündliche Darmerkrankungen. Da Foxp3+ regulatorische T-Zellen nur äußerst geringe Mengen an Interleukin-2 synthetisieren, sind sie auf eine adäquate Versorgung angewiesen. Konventionelle T-Zellen werden als bedeutende IL-2 Quelle für Treg-Zellen vermutet, doch über die Mechanismen und räumlich-zeitliche Dynamik der Treg-Effektor-Zellinteraktion ist bisher nur wenig bekannt.
In dieser Arbeit wurden Foxp3+ regulatorische T-Zellen in Mausgeweben analysiert und Zellinteraktionen mit Effektorzellen im Darm charakterisiert. Es wurde ein theoretisches Modell zur Evaluierung von Zell-Zellkontakten erarbeitet und experimentell überprüft. Es konnte gezeigt werden, dass in der Akutphase einer T-Zell-induzierten Kolitis und im Kolon von gesunden Wildtyp-Mäusen Foxp3+ regulatorische T-Zellen an Ki-67+ proliferierenden T-Zellen akkumulieren. Diese Zellinteraktionen sind abhängig von Interleukin-2, da IL-2 defiziente Mäuse keine signifikanten Treg-Effektor-Zellakkumulationen aufweisen. Die Analyse der Genexpression konnte zeigen, dass Ki-67+ Zellen Interleukin-2 produzieren. Lokal sezerniertes Interleukin-2 könnte als Sensor für Entzündungsprozesse chemotaktisch auf Foxp3+ regulatorische T-Zellen wirken und die Akkumulation an proliferierenden, IL-2 produzierenden Effektorzellen bedingen. Dieser Mechanismus könnte einerseits zur lokalen Versorgung mit IL-2 dienen und gleichzeitig regulierend auf Effektorzellen in unmittelbarer Umgebung wirken. Dieser Prozess würde zur Erhaltung von regulatorischen T-Zellen in der Peripherie und zur Sicherung der intestinalen Immunbalance beitragen.
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Bauch, Michael. "Immunregulation durch mukosale regulatorische Foxp3 positive T-Zellen bei Kindern und Jugendlichen mit Zöliakie." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-96784.
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Zöliakie ist durch eine dysregulierte Immunreaktion auf die in Getreiden enthaltene Proteinfraktion Gluten charakterisiert. Die Assoziation der Erkrankung mit Polymorphismen in immunregulatorischen Genen weist auf eine Rolle von regulatorischen T-Zellen im Krankheitsgeschehen hin. Foxp3+ regulatorische T-Zellen haben eine essentielle Bedeutung für die Aufrechterhaltung der intestinalen Immunhomöostase und die Limitierung von Autoimmunität. In der vorliegenden Arbeit wurde eine 2005 bis 2010 diagnostizierte Gruppe von 51 Kindern und Jugendlichen mit Zöliakie untersucht. Diese Gruppe wurde mit 51 geschlechts- und altersadaptierten Kontrollen ohne Zöliakie verglichen. Es wurden anamnestische, paraklinische und histologische Daten mit der Verteilung von CD3+Foxp3+ regulatorischen T-Zellen in der Dünndarmschleimhaut untersucht. Patienten mit Zöliakie wiesen eine leichte Anämie, jedoch keine signifikante Wachstums- und Gewichtsentwicklung auf, was die oligosymptomatische Verlaufsform in der Gesamtkohorte unterstreicht. Es konnte gezeigt werden, dass CD3+Foxp3+ regulatorische T-Zellen bei Zöliakie-Patienten vermehrt in der Dünndarmschleimhaut akkumulieren. Weiterhin korreliert die Häufigkeit CD3+Foxp3+ regulatorischer T-Zellen sowohl mit dem Schweregrad der Schleimhaut-schädigung (gemessen an der Marsh-Oberhuber-Klassifikation, dem Zotten-Krypten Verhältnis oder der Zahl der intraepithelialen Lymphozyten) als auch mit den Titern Zöliakie-spezifischer Antikörper. Die Akkumulation CD3+Foxp3+ regulatorischer T Zellen lässt sich partiell als Folge einer Anreicherung von CD4+ T-Zellen auf Kosten CD8+ T-Zellen erklären. Die Daten weisen darauf hin, dass Foxp3+ regulatorische T Zellen sekundär als Folge des gluteninduzierten Entzündungsprozesses in der Schleimhaut akkumulieren, diesen offensichtlich aber nicht effektiv begrenzen. Die mögliche Assoziation der Immundysregulation der Zöliakie mit Foxp3+ regulatorischen T-Zellen ist damit nicht durch eine numerische Reduktion sondern wahrscheinlich durch partielle funktionelle Defekte bedingt.
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Lago, Fernanda. "Perfil imunoistoquímico de linfócitos T regulatórios no pênfico foliáceo endêmico através da expressão do marcador Foxp3." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-01122011-194907/.
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Introdução: Os linfócitos T regulatórios CD4+CD25+Foxp3+ (Tregs) desempenham um papel fundamental na manutenção da tolerância aos antígenos próprios e no controle da magnitude da resposta imunológica. Alterações quantitativas ou funcionais foram descritas em diversos distúbios auto-imunes. O pênfigo foliáceo endêmico (PFE) é uma doença bolhosa cutânea de natureza auto-imune, que compartilha características clínicas e imunopatológicas com o pênfigo foliáceo clássico, mas apresenta achados epidemiológicos próprios. Auto-anticorpos circulantes e teciduais da classe IgG dirigidos contra caderinas desmossômicas (desmogleína 1), levam à perda de adesão entre os queratinócitos. Objetivo: O objetivo deste estudo foi avaliar se a perda de tolerância é associada com alterações quantitativas nos linfócitos Tregs CD4+CD25+Foxp3+ na pele de pacientes com PFE. Métodos: Amostras de pele de 22 pacientes e 10 controles saudáveis foram submetidos à análise imunoistoquímica com anti-CD4, anti-CD25 e anti-Foxp3. Fotomicrografias foram obtidas de campos consecutivos ao longo de toda epiderme e derme. A seguir, foi realizada quantificação dos linfócitos Foxp3+, CD4+, CD25+, CD4+Foxp3+ e CD25+Foxp3+ em cada compartimento, considerando-se a respectiva área de cada campo (m2). Valores significantemente estatísticos foram considerados como p<0,05. Resultados: Encontramos um infiltrado epidérmico aumentado de linfócitos imunomarcados CD25+(p=0,003), Foxp3+(p=0,04) e CD25+Foxp3+ (p=0,007), em comparação com os controles. O infiltrado dérmico exibiu uma maior expressão de linfócitos CD4+ (p<0,001) e CD25+ (p=0,008) em amostras de pele de pacientes com PFE, quando comparados aos controles. Conclusões: Nossos achados sugerem que a quebra de tolerância imunológica periférica nos pacientes com PFE não se correlaciona com uma diminuição dos linfócitos T reg CD4+CD25+Foxp3+ na pele afetada. Entretanto, uma maior expressão de linfócitos CD25+Foxp3+ no infiltrado epidérmico poderia representar outra população de linfócitos com atividade regulatória, a ser definida.<br>Background: CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a crucial role in the maintenance of self tolerance and control of the magnitude of the immune response. Their quantitative or functional impairment has been reported in several autoimmune disorders. Endemic pemphigus foliaceus (EPF) is an autoimmune organ-specific blistering skin disorder that shares many clinical and immunopathological features with classic pemphigus foliaceus, but with unique epidemiological features. Circulating and tissue-bound IgG auto-antibodies react against desmosomal cadherins (desmoglein 1), causing loss of adhesion between keratinocytes. Aims: The purpose of this study was to evaluate whether the loss of tolerance is associated with impairment of CD4+CD25+Foxp3+ Tregs in the skin of EPF patients. Methods: Skin samples from 22 patients and 10 controls were submitted to immunohistochemistry with anti-CD4, CD25 and Foxp3. Photomicrographs were obtained from consecutive fields along epidermis and dermis; quantification of Foxp3+, CD4+, CD25+, CD4+Foxp3+ and CD25+Foxp3+ cells were performed in each compartment, taking into account the respective field area (m2). Significance was set at p<0.05. Results: We found an enhanced epidermal infiltrate of CD25+(p=0.003), Foxp3+(p=0.04) and CD25+Foxp3+(p=0.007) immunostained T cells in EPF patients, when compared to controls. Dermal infiltrate exhibited a higher expression of CD4+ (p<0.001) and CD25 p=0.008) T cells in EPF skin samples than in controls. Conclusions: Our findings suggest that the break of peripheral immunologic tolerance in EPF patients did not correlate with an impairment of CD4+CD25+Foxp3+ Treg cells present in the affected skin. However, higher expression of CD25+Foxp3+ cells in the epidermal infiltrate could be a counterpart of a diverse population of T cells, previously described as exerting a regulatory activity, yet to be defined
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Vernes, Sonja. "Investigation of the role of FOXP transcription factors in neurodevelopment." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497468.
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Yao, Edmund. "Effects of DNA methyltrasferase-inhibition on FOXP3 expresssion in CD4+ T cells." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110525.
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ABSTRACTCD4+Foxp3+ regulatory T cells (TREG) are pivotal in the maintenance of immune tolerance to self-antigens and act as regulators of autoimmune reactions. There are two subsets of TREG: naturally occurring (nTREG) which develop in the thymus and inducible (iTREG) which are generated from conventional Foxp3- effector T cells (TCONV) in the periphery or in vitro. While both subsets require Foxp3 expression to function, iTREG cells gradually downregulate Foxp3 in vitro and lose their suppressive capabilities. In contrast, nTREG cells show constitutive Foxp3 expression and demonstrate stable suppressive function in vitro. Recent studies reveal a region of the Foxp3 locus that is differentially methylated between nTREG and iTREG. The methylation-sensitive region, known as the TREG-specific demethylated region (TSDR), is completely unmethylated in nTREG, partially methylated in iTREG, and heavily methylated in TCONV, suggesting that differential methylation patterns of the TSDR may account for unstable Foxp3 expression in iTREG. Methylation is mediated by DNA methyltransferase (DNMTs) enzymes, and several inhibitors are known to block their activity. In this study, we use 5'-Aza-2'-deoxycytidine (Aza), a nucleoside analog inhibitor, and RG108, a non-nucleoside inhibitor to determine whether inhibition of DNMTs and thus methylation, impacts Foxp3 expression and iTREG development in culture. Our results show that DNMT inhibition in the absence of TGF-β was unable to induce Foxp3 expression in TCONV cells. However, in TCONV cells that were pre-exposed to TGF-β, Aza and RG108 induced Foxp3 expression in a significant number of cells. Moreover, a higher proportion of Foxp3-expressing cells with stronger Foxp3 MFI were induced when Aza was used in conjunction with TGF-β suggesting an additive and non-redundant effect of DNMT-inhibition. Although iTREG cells typically downregulate Foxp3 in the absence of TGF-β, treatment with Aza alone prolongs the persistence of Foxp3 expression. Neither Aza nor RG108 was as effective as TGF-β in maintaining Foxp3 expression. Collectively, our data shows that DNMT inhibition without TGF-β is insufficient to induce Foxp3 expression but in conjunction, can increase induction and strengthen Foxp3 expression. DNMT inhibition can also prolong Foxp3 expression in the absence of TGF-β possibly by disrupting epigenetic silencing mechanisms.<br>ABRÉGÉLes lymphocytes T régulateurs CD4+Foxp3+ (TREG) sont des pivots dans le maintien de la tolérance immunitaire aux antigènes autologues et agissent en tant que régulateurs des réactions auto-immunes. Il y a deux sous-ensembles de TREG : les naturelles (nTREG) qui se développent dans le thymus et les inductibles (iTREG) qui sont générés à partir des lymphocytes T effecteurs Foxp3- conventionnels (TCONV) en périphérie ou in vitro. Bien que les deux sous-ensembles requièrent l'expression de Foxp3 pour fonctionner, les lymphocytes iTREG régulent graduellement de manière négative Foxp3 in vitro et perdent leur capacité suppressive. En revanche, les lymphocytes nTREG présentent une expression constitutive de Foxp3 et démontrent une fonction suppressive stable in vitro. Des études récentes révèlent une région du locus Foxp3 qui est différentiellement méthylée entre les nTREG et les iTREG. La région sensible à la méthylation, connue sous le nom de la région déméthylée spécifique à TREG (TREG-specific demethylated region, TSDR), est complètement non méthylée dans les nTREG, partiellement méthylée dans les iTREG, et fortement méthylée dans les TCONV. Cela suggère que les modèles de méthylation différentielle du TSDR pourraient expliquer l'expression instable de Foxp3 dans les iTREG. Les enzymes ADN méthyltransférases (DNA methyltransferases, DNMTs) servent de médiatrices dans la méthylation, et quelques inhibiteurs sont connus pour bloquer leur activité. Dans cette étude, nous utilisons le 5'-Aza-2'-déoxycytidine (Aza), un inhibiteur analogue nucléosidique, et RG108, un inhibiteur non-nucléosidique, pour déterminer si l'inhibition des DNMTs et ainsi la méthylation, aurait un impact sur l'expression de Foxp3 et le développement de iTREG en culture. Nos résultats montrent que l'inhibition de DNMT en l'absence de TGF-β n'a pas pu induire l'expression de Foxp3 dans les lymphocytes TCONV. Toutefois, dans les lymphocytes TCONV qui étaient pré-exposés au TGF-β, Aza et RG108 ont induit l'expression de Foxp3 dans un nombre important de lymphocytes. De plus, une proportion plus grande de lymphocytes exprimant le Foxp3 avec un Foxp3 MFI plus élevé étaient induits lorsque Aza était utilisé conjointement avec TGF-β, suggérant un effet additif et non redondant de l'inhibition de DNMT. Malgré que les lymphocytes iTREG régulent généralement de façon négative Foxp3 en l'absence de TGF-β, le traitement par Aza seul prolonge la persistance de l'expression de Foxp3. Ni Aza, ni RG108 n'est aussi efficace que TGF-β dans le maintien de l'expression de Foxp3. En somme, nos données montrent que l'inhibition de DNMT sans TGF-β est insuffisant pour induire l'expression de Foxp3, mais que conjointement, peut en augmenter l'induction et la renforcer. L'inhibition de DNMT peut également prolonger l'expression de Foxp3 en l'absence de TGF-β possiblement en perturbant les mécanismes d'inhibition épigénétique.
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Elahi, Mojdeh Fanny. "Functional studies of FOXP2-gene involved in brain development and language acquisition." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531813.
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Marticke, Simone Sigrid. "Ultra-high throughput sequencing analysis of FOXP2 occupancy in the human genome /." May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Cuss, Steven Martin. "The CD40-CD154 pathway in the development of Foxp3⁺ regulatory T cells." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610532.
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Marguti, Ivo. "Efeito das células dendríticas na geração de células T CD4+CD25+Foxp3+." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-18102007-154828/.
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As células dendríticas (DCs) são as principais células apresentadoras de antígeno do sistema imune. No entanto, trabalhos têm demonstrado seu envolvimento na manutenção da tolerância imunológica. As células T CD4+CD25+Foxp3+ possuem a capacidade de suprimir respostas imunes. Neste estudo avaliamos as alterações ocorridas na população de células T CD4+CD25+Foxp3+ após co-cultura de células de linfonodo com DCs. Nossos resultados demonstram que após a co-cultura há um aumento da população de células CD4+CD25+Foxp3+ de maneira independente do estado de ativação das DCs ou da presença de antígenos exógenos. No entanto, o aumento observado é maior quando DCs imaturas são incubadas com antígenos exógenos. Notamos ainda que há presença de TGF-ß em todas as condições experimentais em que observamos aumento da população de células CD4+CD25+Foxp3+. Nossos dados sugerem ainda que este aumento se deve à proliferação das células T CD4+CD25+Foxp3+.<br>Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system. However, DCs have also been implicated in maintaining immunologic tolerance. CD4+CD25+Foxp3+ T lymphocytes are known as cells with regulatory properties. In this study we evaluated the changes in the CD4+CD25+Foxp3+ T cell population after co-culture of lymph-node cells with DCs. Our results show an increase in the CD4+CD25+Foxp3+ T cell population after co-culture and occurs regardless of the activation state of DCs and the presence of exogenous antigens; however it is greater when immature DCs are previously pulsed with exogenous antigen. We also noticed that TGF-? is present in all cultures conditions in which the CD4+CD25+Foxp3+ T cell population increases. Our data also suggests that the increase of the CD4+CD25+Foxp3+ T cell population may be due to the proliferation of these cells.
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Cassan, Cécile. "Lymphocytes T CD4+Foxp3+ régulateurs et auto-immunité du système nerveux central." Toulouse 3, 2006. http://www.theses.fr/2006TOU30184.
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Le système immunitaire nous défend contre les pathogènes, tandis que plusieurs mécanismes, notamment le contrôle exercé par les lymphocytes T CD4+CD25+Foxp3+ régulateurs (Tregs), concourent au maintien de la tolérance immunitaire vis-à-vis des antigènes de l'organisme. Une rupture de tolérance aboutit au développement de maladies auto-immunes, telles que la sclérose en plaques (SEP). Nous avons montré le rôle protecteur des Tregs contre le développement de l'encéphalomyélite auto-immune expérimentale (EAE), modèle animal de SEP. Puis nous avons étudié le rôle du thymus et des antigènes du soi dans la génération de Tregs spécifiques d'antigènes du système nerveux central, et leur spécificité dans le cadre de l'EAE. A l'avenir, une meilleure connaissance des Tregs permettra de concevoir de nouvelles stratégies pour le traitement de la SEP<br>The immune system defends us against invasions of pathogens; meanwhile, several mechanisms, including the control exerted by CD4+CD25+Foxp3+ regulatory T lymphocytes (Tregs), maintain an immune tolerance towards self-antigens. A disruption of this tolerance contributes to the development of auto-immune diseases, such as multiple sclerosis (MS). We have showed that Tregs protect mice against the development of experimental auto-immune encephalomyelitis (EAE), which is an animal model for MS. We have then investigated the role of the thymus and of self-antigens in the generation of Tregs specific for central nervous system antigens, as well as their specificity in EAE. A better knowledge on Tregs will allow the design of new therapeutic strategies for MS patients
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Kotey, Amos. "Newly Identified Role for the Transcription Factor Foxp1 in Natural Killer Cells." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627658577374061.
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Akbar, Haroon. "Rôle des cellules T régulatrices dans un modèle murin de toxoplasmose aigüe." Thesis, Tours, 2011. http://www.theses.fr/2011TOUR3803/document.
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Une immunité concomitante à long terme est mise en place lors d’infections persistantes avec des parasites protozoaires intracellulaires responsables, par exemple, de la leishmaniose et du paludisme. Dans un modèle murin de leishmaniose, il a ainsi été démontré que les cellules T régulatrices CD4+CD25+ sont impliquées dans la persistance des leishmanies aux sites d’infection cutanés et protègent l’hôte contre une ré-infection.Le protozoaire Toxoplasma gondii est également à l’origine d’une infection chronique liée à l’installation du parasite dans le cerveau et les muscles de l’hôte dans des formes kystiques. Il était donc pertinent de s’intéresser à l’implication des cellules T régulatrices dans l’installation et la persistance du toxoplasme.Pour atteindre cet objectif, nous avons utilisé l’anticorps monoclonal anti-CD25 dans des expériences de déplétion pendant la phase aiguë de la toxoplasmose après infection de souris non consanguines avec une souche de toxoplasmes de type II. Aucune différence significative que ce soit en terme de mortalité ou de charge parasitaire cérébrale n’a été observée entre les souris infectées et déplétées et les souris infectées non déplétées. En complément de ces expériences, nous avons pu montrer que les cellules régulatrices CD4+CD25+Foxp3+ (Treg) sont une cible potentielle de l’anticorps anti-CD25 ainsi que les cellules T effectrices CD4+CD25+Foxp3- (Teff); cellules qui expriment le marqueur CD25 en phase aiguë de l’infection<br>Long term concomitant immunity is developed in case of persistant infections with intracellular protozoan parasites like for example in leishmaniosis and malaria. In a murine model of leishmaniosis, it has been demonstrated that CD4+CD25+ regulatory T (Treg) cells are involved in the persistance of leishmania parasites at cutaneous sites of infection and protect the host against re-infection.The protozoan parasite Toxoplasma gondii is also responsible for a chronic infection associated with the settlement of parasite in the brain and the muscles of the host in the form of cysts. It was therefore pertinent to know about the implication of Treg cells in the development and the persistance of toxoplasma. To attain this objective, we have used a monoclonal antibody anti-CD25 in depletion experiments during the acute phase of toxoplasmosis after infection of outbred mice with a type II toxoplasma strain. No significant difference was found in terms of mortality or in brain cyst load between depleted mice and non-depleted mice. In addition to these experiments, we have shown that not only the CD4+CD25+Foxp3+ regulatory T (Treg) cells but also the CD4+CD25+Foxp3- T effector (Teff) cells are a potential target of anti-CD25 antibody-depletion. These cells are induced to express CD25 during acute phase of the infection
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Döbbeler, Marina [Verfasser], Alexander [Akademischer Betreuer] Steinkasserer, and Falk [Gutachter] Nimmerjahn. "Die endogene CD83 Expression auf Foxp3+ T-Zellen ist essenziell für die Differenzierung und Funktion muriner Foxp3+ regulatorischer Effektor-T-Zellen / Marina Döbbeler ; Gutachter: Falk Nimmerjahn ; Betreuer: Alexander Steinkasserer." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2018. http://d-nb.info/1169399061/34.
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