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1
Carson, Bryan David. "Impaired T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8337.
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Lloyd, Angharad. "Gene editing in T-cells and T-cell targets." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/98512/.
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Recent years have witnessed a rapid proliferation of gene editing in mammalian cells due to the increasing ease and reduced cost of targeted gene knockout. There has been much excitement about the prospect of engineering T-cells by gene editing in order to provide these cells with optimal attributes prior to adoptive cell therapy for cancer and autoimmune disease. I began by attempting to compare short hairpin RNA (shRNA) and zinc finger nuclease (ZFN) approaches using the CD8A gene as a target for proof of concept of gene editing in Molt3 cells. During the course of my studies the clustered regularly interspaced short palindromic repeats (CRISPR) mechanism for gene editing was discovered so I also included CRISPR/Cas9 in my studies. A direct comparison of the three gene editing tools indicated that the CRISPR/Cas9 system was superior in terms of ease, efficiency of knockout and cost. As the use of gene editing tools increases there are concerns about the inherent risks associated with the use of nuclease based gene editing tools prior to cellular therapy. Expression of nucleases can lead to off target mutagenesis and malignancy. To circumvent this problem I generated a non-nuclease based gene silencing system using the CD8A zinc finger (ZF) fused to a Krüppel associated box (KRAB) repressor domain. The ZF-KRAB fusion resulted in effective silencing of the CD8A gene in both the Molt3 cell line and in primary CD8+ T-cells. Importantly, unlike CRISPR/Cas9 based gene editing, the ZF-KRAB fusion was small enough to be transferred in a single lentiviral vector with a TCR allowing simultaneous redirection of patient T-cell specificity and alteration of T-cell function in a single construct. To improve the efficiency of gene editing with CRISPR/Cas9 I developed an ‘all in one’ CRISPR/Cas9 system which incorporated all elements of the CRISPR/Cas9 gene editing system in a single plasmid. The ‘all in one’ system was utilised to derive MHC-related protein 1 (MR1) deficient clones from the A549 lung carcinoma and THP-1 monocytic cell lines in order to study MR1 biology. Mucosal-associated invariant T-cell (MAIT) clones were not activated by MR1 deficient A549 or THP-1 clones infected with bacteria.
3
Stefkova, Martina. "Regulatory T cells control the CD4 T cell repertoire." Doctoral thesis, Universite Libre de Bruxelles, 2016. https://dipot.ulb.ac.be/dspace/bitstream/2013/233151/3/Table.pdf.
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Des études récentes menées chez l’homme et la souris ont suggéré que la diversité du répertoire TCR pourrait jouer un rôle dans la protection contre des pathogènes à haut pouvoir mutagène. Afin d’étudier le répertoire des lymphocytes T CD4, nous avons utilisé un modèle de souris TCRβ transgéniques exprimant une chaine β spécifique du peptide env122-141 dans le contexte du MHCII. Suite à l’immunisation des souris TCRβ transgéniques avec des cellules dendritiques pulsées avec le peptide env, une rapide prolifération et une restriction du répertoire des lymphocytes T Vα2 CD4 spécifiques est observée. L’analyse de la diversité du répertoire de ces cellules par séquençage à haut débit, a montré l’émergence d’un répertoire plus divers dans des souris déplétées en lymphocytes T régulateurs. Ces résultats suggèrent qu’en plus du rôle des Tregs dans le contrôle de la magnitude de la réponse immunitaire, ces cellules pourraient également contrôler la diversité du répertoire des lymphocytes T suite à une stimulation antigénique.Recent studies conducted in mice and humans have suggested a role for the TCR repertoire diversity in immune protection against pathogens displaying high antigenic variability. To study the CD4 T cell repertoire, we used a mouse model in which T cells transgenically express the TCRβ chain of a TCR specific to a MHCII-restricted peptide, env122-141. Upon immunization with peptide-pulsed dendritic cells, antigen-specific Vα2+ CD4+ T cells rapidly expand and display a restricted TCRα repertoire. In particular, analysis of receptor diversity by high-throughput TCR sequencing in immunized mice suggests the emergence of a broader CDR3 Vα2 repertoire in Treg-depleted mice. These results suggest that Tregs may play a role in the restriction of the CD4 T cell repertoire during an immune response, raising therefore the possibility that in addition to controlling the magnitude of an immune response, regulatory cells may also control the diversity of TCRs in response to antigen stimulation.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Butcher, Sarah A. "T cell receptor genes of influenza A haemagglutinin specific T cells." Thesis, University College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315271.
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Crawford, A. "How B cells influence T cell responses." Thesis, University of Edinburgh, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.645118.
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Although studies using B cell deficient mice have been useful in understanding the importance of B cells under different conditions, it is difficult to then dissect exactly how B cells could be regulating T cell responses. By transferring OT-II transgenic T cells into either B cell deficient (μMT) or C57BL/6 mice, expansion and contraction of T cells can be tracked ex vivo. Expansion of OT-II cells is reduced in μMT mice compared to C57BL/6 mice. Thus, B cells can provide costimulatory signals, secrete cytokines and influence the lymphoid microarchitecture. To dissect which B cell factor(s) are involved in enhancing OT-II T cell expansion, a model system was used where one molecule on the B cells is depleted at one time. This was achieved by creating bone-marrow chimeras using a combination of μMT bone-marrow and wildtype or deficient bone-marrow. Thus, all the B cells are either wildtype or deficient for a particular molecule. The molecules examined were MHC-II, which is required for antigen presentation, CD40, due to its costimulatory role, and lymphotoxin-alpha, for its role in maintenance of splenic architecture. Using the OT-II adoptive transfer system, we have shown a requirement for MHC-II but not CD40 on B cells for efficient T cell expansion. In light of these observations, the role of B cell-derived MHC-II for T cell memory generation was examined. To do this, I used MHC-II tetramers to track a polyclonal population of T cells in the host. Using this technique, I have shown that T cell memory is also diminished when the B cells do not express MHC-II. Thus, a cognate interaction with B cells is required for both efficient expansion and memory generation of CD4+ T cells.
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Sarris, Milka. "Dynamics of helper T cell and regulatory T cell interactions with dendritic cells." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611896.
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Smith, Trevor Robert Frank. "Modulation of CD4+ T cell responses by CD4+CD25+ regulatory T cells and modified T cell epitopes." Thesis, Imperial College London, 2004. http://hdl.handle.net/10044/1/11317.
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Murray, Nicholas. "Costimulation of T cells and its role in T cell recognition of malignant colorectal cells in vitro." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301247.
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Li, Ming 1957. "Generation of CD8+ T cell immunity with help from CD4+ T cells." Monash University, Dept. of Pathology and Immunology, 2002. http://arrow.monash.edu.au/hdl/1959.1/8476.
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Soper, David Michael. "Interleukin-2 receptor and T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8344.
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Sommermeyer, Daniel. "Generation of dual T cell receptor (TCR) T cells by TCR gene transfer for adoptive T cell therapy." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16051.
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Die Herstellung von T-Zellen mit definierten Spezifitäten durch den Transfer von T-Zellrezeptor (TCR) Genen ist eine effiziente Methode, um Zellen für eine Immuntherapie bereitzustellen. Eine besondere Herausforderung ist dabei, ein ausreichend hohes Expressionsniveau des therapeutischen TCR zu erreichen. Da T-Zellen mit einem zusätzlichen TCR ausgestattet werden, entsteht eine Konkurrenzsituation zwischen dem therapeutischen und dem endogenen TCR. Bevor diese Arbeit begonnen wurde war nicht bekannt, welche TCR nach einem Gen-Transfer exprimiert werden. Daher haben wir Modelle etabliert, in denen TCR Gene in Maus und humane T-Zellen mit definierten endogenen TCR transferiert wurden. Die Expression beider TCR wurde mithilfe von Antikörpern und MHC-Multimeren analysiert. Diese Modelle haben gezeigt, dass bestimmte TCR andere TCR von der Zelloberfläche verdrängen können. Dies führte in einem Fall zu einer vollständigen Umkehr der Antigenspezifität. Aufgrund dieser Ergebnisse haben wir das Konzept von „starken“ (gut exprimierten) und „schwachen“ (schlecht exprimierten) TCR vorgeschlagen. Zusätzlich wurde die Verdrängung „schwacher“ und „starker“ humaner TCR durch Maus TCR beobachtet. Parallel dazu wurde berichtet, dass die konstanten (C) Regionen von Maus TCR für die erhöhte Expression auf humanen Zellen verantwortlich sind. Dies führte zu einer Strategie zur Verbesserung der Expression humaner TCR, die auf dem Austausch der humanen C-Regionen durch die von Maus TCR basiert (Murinisierung). Ein Problem ist dabei die mögliche Immunogenität dieser hybriden Konstrukte. Deshalb haben wir jene Bereiche der Maus C-Regionen identifiziert, die für die erhöhte Expression verantwortlich sind. In der TCRalpha Kette wurden vier und in der TCRbeta Kette fünf Aminosäuren gefunden, die ausreichend für diesen Effekt waren. Primäre humane T-Zellen mit TCR, die diese neun „Maus“ Aminosäuren enthielten, zeigten eine bessere Funktionalität als T-Zellen mit Wildtyp TCR.The in vitro generation of T cells with a defined antigen specificity by T cell receptor (TCR) gene transfer is an efficient method to create cells for immunotherapy. One major challenge of this strategy is to achieve sufficiently high expression levels of the therapeutic TCR. As T cells expressing an endogenous TCR are equipped with an additional TCR, there is a competition between therapeutic and endogenous TCR. Before this work was started, it was not known which TCR is present on the cell surface after TCR gene transfer. Therefore, we transferred TCR genes into murine and human T cells and analyzed TCR expression of endogenous and transferred TCR by staining with antibodies and MHC-multimers. We found that some TCR have the capability to replace other TCR on the cell surface, which led to a complete conversion of antigen specificity in one model. Based on these findings we proposed the concept of ‘‘strong’’ (well expressed) and “weak” (poorly expressed) TCR. In addition, we found that a mouse TCR is able to replace both “weak” and “strong” human TCR on human cells. In parallel to this result, it was reported that the constant (C)-regions of mouse TCR were responsible for the improved expression of murine TCR on human cells. This led to a strategy to improve human TCR by exchanging the C-regions by their murine counterparts (murinization). However, a problem of these hybrid constructs is the probable immunogenicity. Therefore, we identified the specific parts of the mouse C-regions which are essential to improve human TCR. In the TCRalpha C-region four and in the TCRbeta C-region five amino acids were identified. Primary human T cells modified with TCR containing these nine “murine” amino acids showed an increased function compared to cells modified with wild type TCR. For TCR gene therapy the utilization of these new C-regions will reduce the amount of foreign sequences and thus the risk of immunogenicity of the therapeutic TCR.
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Nadal-Melsio, Elisabet. "Regulatory T cells after allogeneic stem cell transplantation." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523746.
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Mahajan, Simmi. "Development of T cell help for B cells." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/12548.
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Mavin, Emily. "Regulatory T cells in haematopoietic stem cell transplantation." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2731.
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Graft-versus-host disease (GvHD) remains the main complication associated with haematopoietic stem cell transplantation (HSCT). GvHD is caused by allo-reactive donor T cells mounting an attack against specific target tissues. CD4+CD25HiFoxp3+ regulatory T cells have been shown to modulate GvHD in vitro and also in vivo animal models. More recently early stage clinical trials have described the successful use of Treg to reduce the incidence of GvHD following HSCT. The aim of this study was to investigate further the suppressive mechanisms by which Treg are able to modulate GvHD and assess the influence of Treg on the beneficial graft-versus-leukaemia (GvL) effect therefore providing further insight into the use of Treg in the therapeutic management of GVHD. Data presented in this thesis demonstrates the successful isolation and expansion of a highly pure Treg population which maintained suppressive capacity throughout culture. We also confirmed that Treg retain suppressive capacity following cryopreservation resulting in reduced workload and increased consistency when used for in vitro functional studies. We also provide the first human in vitro evidence that Treg are able to prevent cutaneous GvH reaction by blocking the migration of effector T cells into the target tissues. The presence of Treg during allo-stimulation caused reduced effector cell activation, proliferation, IFNγ secretion and decreased skin homing receptor expression. Further investigation into the Treg modulation of dendritic cells demonstrated, for the first time in experimental in vitro human GvHD, that this was due to ineffective effector T cell priming in the presence of Treg caused by impairment of dendritic cell functions. Comprehensive phenotypic and functional analysis of Treg treated moDC showed their decreased antigen processing ability and allostimulatory capacity, resulting in a less severe GvH reaction in the skin explant model. Furthermore, this work has revealed that despite Treg impairing in vitro GvL mechanisms at a cellular level there was no association observed between increased Treg levels and the incidence of relapse in a small clinical cohort of HSCT patients. In conclusion this study has provided further insight into the mechanisms by which Treg are able to modulate GvHD. This would inform future clinical trials using Treg as a therapeutic alternative to current GvHD treatment and prophylaxis.
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Robertson, Anna-Karin L. "T cells in atherogenesis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-032-X/.
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Robb, S. A. "T cells in myasthenia." Thesis, University of Newcastle Upon Tyne, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376234.
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Cabbage, Sarah E. "Reversible regulatory T cell-mediated suppression of myelin basic protein-specific T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5034.
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Wright, G. P. "Generation of antigen-specific regulatory T cells by T cell receptor gene transfer." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18952/.
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Regulatory T cells (Tregs) have shown considerable potential in the treatment of murine models of immuno-pathology. Whilst poly-clonal Tregs are able to suppress immuno-pathology in a number of models, the superiority of Ag-specific Treg treatment has been demonstrated using Tregs from T cell receptor (TCR)- transgenic animals. Translation of these promising results to the clinic has been hampered by difficulties in isolating or enriching the rare Ag-specific Tregs from the polyclonal population. Here I describe two distinct approaches to generate Ag-specific T cells with regulatory ability: firstly, TCR gene transfer into purified CD4+CD25+ T cells was used to redirect the specificity of naturally occurring Tregs. Secondly, co-transfer of FoxP3 and TCR genes served to convert conventional CD4+ T cells into Ag-specific ‘Treg-like’ cells. Both approaches generated T cells that suppressed in vitro and engrafted efficiently, retaining TCR and FoxP3 expression, when adoptively transferred into recipient mice. Using an established arthritis model, I demonstrate Ag-driven accumulation of the gene modified T cells at the site of joint inflammation, which resulted in a reduction of joint swelling. In animals treated with TCR-transferred natural Tregs this was accompanied by a local reduction in the number of inflammatory Th17 cells and a significant decrease in arthritic bone destruction. Together, I have described a strategy to rapidly generate Ag-specific Tregs capable of antigen-dependent amelioration of autoimmune damage in the absence of general immune suppression. These approaches could practicably be translated into the clinic in order to treat numerous different immuno-pathologies.
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Nagai, Yuya. "T memory stem cells are the hierarchical apex of adult T-cell leukemia." Kyoto University, 2015. http://hdl.handle.net/2433/202670.
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Terry, Alexandra Margaret. "The Roles of CD4+ T cells and Regulatory T cells in Antitumour Immunity." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/17331.
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Although the immune system is rapidly becoming a key target for cancer treatment we still lack a comprehensive understanding of how the immune system affects cancer progression. Animal models, such as the one used in this thesis, help to delineate the complex feedback interactions between the immune system and cancer and to identify novel cellular and molecular targets for anticancer drugs. The negative role of regulatory T cells (Tregs) in cancer is well but their mechanism and cellular targets are not fully understood. This thesis uses a novel transgenic mouse model to establish how tumour-specific thymic Tregs (tTregs) and peripheral Tregs (pTregs) affect CD4+ T cell mediated tumour immunity and consequently altering the tumour microenvironment. Tumour-specific CD4+ T cells eradicated subcutaneous B16 melanoma despite a lack of direct interaction with tumour cells due to MHCII mismatch. Tumour rejection was driven by IFNγ+TNFα+IL2+ Th1 cells and was associated with neutrophil influx into the tumour. In some animals tumours recurred in the context of reduced Th1 and early CD4+ T cell conversion into pTregs, yet pTreg depletion did not trigger tumour rejection. Thymic Tregs suppressed CD4+ T cell-mediated tumour rejection in an antigen-dependent manner by reducing Th1 expansion. The response was rescued if tTregs were depleted from hosts prior to CD4+ T cell priming. Analysis of the tumour microenvironment identified several subsets of antigen-presenting cells (APCs) capable of presenting tumour antigen to CD4+ T cells ex vivo. Three previously unappreciated distinct dendritic cell (DC) populations (CD11b+, CD103+ and CD103-) were characterised and shown to have superior antigen-presenting capacity. CD4+ T cell transfer led to upregulation of both costimulatory and inhibitory markers on tumour APCs, while tTregs suppressed DC costimulation. These findings reported advance our understanding of the complex immune feedback mechanisms that control cancer progression.
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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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Javorovic, Miran. "T-Cell Stimulation by Melanoma RNA-Pulsed Dendritic Cells." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-30569.
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Bansal, Raj Rani. "B cell help provided by human γδ T cells." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/36649/.
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Vγ9Vδ2 T cells are a minor subset of T cells in human blood that differ from all other lymphocytes by their specific responsiveness to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a metabolite produced by a large range of microbial pathogens. Vγ9Vδ2 T cells can be skewed towards distinct effector functions, in analogy to, and beyond, the emerging plasticity of CD4+ T cells. Depending on the microenvironment, Vγ9Vδ2 T cells can assume features reminiscent of Th1, Th2, Th17 and Treg cells as well as professional antigen presenting cells (APCs). The main focus of this PhD was to investigate the role of the follicular B helper T (Tfh) cell derived cytokine IL-21 in enhancing the ability of human Vγ9Vδ2 T cells in providing B cell help. In order to try to mimic the physiological conditions in the GC, an in vitro system of autologous Vγ9Vδ2 T cells and B cells from tonsils or blood, the microbial metabolite HMB-PP and IL-21 was used. HMB-PP induced up-regulation of IL-21 receptor on Vγ9Vδ2 T cells. In return, IL-21 played a co-stimulatory role in the expression of the B cell-attracting chemokine CXCL13, the CXCL13 receptor CXCR5, the co-stimulatory molecules inducible co-stimulator (ICOS), OX40 and CD70 by activated Vγ9Vδ2 T cells. IL-21 also enhanced the ability of activated Vγ9Vδ2 T cells to support antibody production by B cells. Furthermore, Vγ9Vδ2 T cells not only themselves became highly activated APC marker expressing cells but also modified activation and APC marker expression on B cells. Findings presented in this thesis provide evidence that IL-21 contributes to the acquisition of B cell helper functions by human Vγ9Vδ2 T cells. In secondary lymphoid tissues, the interaction between HMB-PP-responsive Vγ9Vδ2 T cells, IL-21-producing Tfh cells and B cells is likely to impact on the generation of high affinity, class-switched antibodies in microbial infections
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Crawford, Alison. "Role of B cells in influencing T cell responses." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/13483.
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Mulati, Kumuluzi. "VISTA expressed in tumor cells regulates T cell function." Kyoto University, 2019. http://hdl.handle.net/2433/242370.
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Raeiszadeh, Mohammad. "Reconstitution of CMV-specific T-cells following adoptive T-cell immunotherapy and haematopoietic stem cell transplantation." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6968/.
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This thesis investigated reconstitution of CMV-specific T-cells in two cohorts of HSCT patients and studied the potential role of Tumour Necrosis Factor Receptor 2 (TNFR2) in regulation of CMV-specific T-cell expansion post HSCT. The first cohort included patients of a randomized phase II trial of adoptive cellular therapy for CMV-specific CD8\(^+\) T-cells. Cellular therapy resulted in earlier and greater expansion of CMV-specific CD8\(^+\) T cells and also reconstitution of CMV-specific CD4\(^+\) and non-infused CMV-specific CD8\(^+\) T-cells. The number of infused therapeutic T-cells and circulating levels of Alemtuzumab were found to influence immunotherapy. Additionally, reconstitution of CMV-specific CD4\(^+\) T-cells was studied using HLA-class II tetramers. CMV-specific CD4\(^+\) T-cell count of >0.7x10\(^3\)/ml was found to protect from recurrent CMV reactivation. One third of specific CD4\(^+\) T-cells were perforin and granzyme-B positive indicating cytotoxic potential, whilst the majority expressed T-bet. Expression of CD57 molecule on CD4\(^+\) T-cells was demonstrated as a potential biomarker of immune response to CMV. Also, distinct cytokine receptor expression patterns in naïve versus memory T-cells were observed. The results showed rapid decrease in IL-6R and increase in expression of TNFR2 after T-cell differentiation from naïve to effector cells and engagement of TNFR2 led to the apoptosis of CMV-specific T-cells.
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Kanazawa, Nobuo. "Fractalkine and macrophage-derived chemokine : T cell attracting chemokines expressed in T cell area dendritic cells." Kyoto University, 2000. http://hdl.handle.net/2433/180886.
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Himmel, Megan Elizabeth. "Phenotypic and functional characterization of T cells and Foxp3⁺ T regulatory cells in inflammatory bowel disease : steps towards T regulatory cell therapy in mucosal disease." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42517.
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Because of their potent suppressive capacity and critical role in the normal function of the human immune system, T regulatory cells (Tregs) have long been considered candidates for the therapeutic treatment of autoimmune and chronic inflammatory diseases. However, the clinical implementation of these cells has proven challenging in practice, in part due to a lack of knowledge surrounding this T cell subset. Specifically, an evaluation of the unique functions of individual Treg cell lineages, along with a comprehensive investigation of the non-suppressive capacities of these cells, including chemokine production, is necessary. Furthermore, in the application of Treg cellular therapy in mucosal diseases such as inflammatory bowel disease, the identification of putative antigens that can be targeted by Tregs is warranted. To these aims, I evaluated the phenotypic and functional characteristics of Helios⁺ and Helios⁻ Treg subsets, with the knowledge that expression of Helios, an Ikaros family transcription factor, may differentiate natural, thymic derived Tregs from their in vivo peripherally induced counterparts. I found that Helios positive and negative Treg subsets expressed similar Treg markers and displayed a similar capacity for suppression and plasticity. However, these Tregs did differ in terms of cytokine/chemokine production as well as methylation state of the FOXP3 Treg-specific demethylated region. Futhermore, total populations of FOXP3⁺ Tregs were evaluated for chemokine expression; I found that Tregs produce significant quantities of CXCL8 and other acute phase chemokines, and are able to attract inflammatory cells of the innate immune system. In addition, FOXP3 expression enhances CXCL8 production, likely because of its ability to bind the CXCL8 gene promoter. To evaluate putative antigens that can be targeted by Treg therapy in inflammatory bowel disease, I assessed the role of flagellin in disease. Flagellin exacerbates colitic disease in mice in a TLR5 independent manner and flagellin-specific T cells can be identified in patients with CD. Collectively, these findings bring us closer to the effective application of Treg cellular therapy in the setting of mucosal disease.
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Ye, Song Cheung H. Tak. "Identification of a thymic extracellular matrix protein that promotes strong thymocyte adhesion." Normal, Ill. Illinois State University, 1990. http://wwwlib.umi.com/cr/ilstu/fullcit?p9115234.
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Thesis (Ph. D.)--Illinois State University, 1990.Title from title page screen, viewed December 2, 2005. Dissertation Committee: H. Tak Cheung (chair), Herman Brockman, Harry Huizinga, Anthony Otsuka, Brian Wilkinson. Includes bibliographical references (leaves 116-127) and abstract. Also available in print.
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Salcido-Ochoa, Francisco. "Anergic T cells & immunoregulation." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418002.
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Taylor, P. M. "Cytotoxic T-cells in influenza." Thesis, Brunel University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234171.
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Mottet, Christian. "Biology of regulatory T cells." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433353.
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Thompson, Claire. "Characterisation of regulatory T cells." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436941.
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Hildalgo, Ester. "T cells in Rheumatoid Arthritis." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1715/.
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Identification of the role of T cells and their interaction with other cell types remains a major challenge to our understanding of the pathogenesis of rheumatoid arthritis. In this study we have investigated the regulation of the response of T cells infiltrating the rheumatoid joint to IL-6. Furthermore we have investigated the level of T cell activation in the early stages of rheumatoid arthritis. Interleukin-6 is an important regulator of T cell differentiation and survival. It exerts its biological function by either directly binding to the complete IL-6 receptor consisting of CD126 CD130 or via transsignaling, when sIL6R-IL6 complexes bind to CD130. This study addresses the expression and regulation of these receptor components on the T cells infiltrating the rheumatoid joint. While compared to blood T cells, CD126 expression was found at low levels on synovial fluid and tissue T cells, expression of CD130 on synovial tissue T cells was comparable to that of blood T cells, with lower levels in synovial fluid T cells, both at protein and mRNA level. When exposed to sIL6R-IL6 complexes, tissue derived T cells responded with a higher level of STAT3 phosphorylation compared to cells incubated with IL-6, suggestive of transsignaling. High CD130 expression was demonstrable in T cells in the perivascular cuff area. Among a range of cytokines tested, IL-6 reduced CD126 and CD130 expression while IL-10, which is expressed at high levels in the perivascular infiltrate, induced expression of CD130. Taken together these data suggest that the inflammatory microenvironment maintains responsiveness to IL-6 transsignalling by cytokine driven CD130 expression on CD4 positive T cells. To address the question whether the role of T cells changes during the course of progression of RA, we analysed the expression of T cells activation markers on synovial fluid and peripheral blood T cells from patients at the very early stage of disease (within 3 months of disease onset) compared to patients with established or self resolving arthritis. Expression of CD69, CD71 and HLA-DR was upregulated on synovial fluid T cells compared to peripheral blood but there were no differences between the different groups of patients. Furthermore, we quantified the proportion of T cells expressing the invariant TCR Vα24Jα18 in synovial fluid and blood of the same groups of patients. We found a lower frequency of iNKT cells in the synovial fluid of very early arthritis patients compared to other patients. While this is a preliminary result, it suggests that there may be a role for these cells in the regulation of disease susceptibility.
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Aloufi, Nawaf. "The role of sCD127 in IL-7-Mediated T Cell Homeostasis in Vivo." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41089.
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Interleukin-7 is an essential cytokine that plays a major role in the development and homeostatic maintenance of T-cells. The presence of soluble forms of various cytokine receptors have been proposed to be involved in the endogenous regulation of cytokine activity. Due to the natural ability of soluble CD127 (sCD127) to bind to IL-7, there is an interest in its potential application as an immunotherapeutic agent in diseases, where IL-7 has been found to be relevant, including HIV infection. In this study, I hypothesize that by administering sCD127 to healthy mice, IL-7 activity should be enhanced, thus enhancing T cell proliferation in vivo.
The work presented here focuses on three main objectives: 1) evaluating the effect of IL-7 with or without sCD127 on T cell proliferation in healthy mice; 2) validating a mouse model of T cell depletion using anti-CD4 and CD8 antibodies; and 3) determining the effect of sCD127 treatment with or without IL-7 on T cell reconstitution and proliferation in the T cell depletion model. To assess the effect of administering exogenous sCD127, IL-7 or the combination on T cell proliferation, peripheral blood mononuclear cells and spleen were isolated, and stained to characterize T cell number, proliferation, and surface CD127 expression by flow cytometry. For the T cell depletion model, wild type C57BL/6 mice were injected intra-peritoneally with 150 μg single dose of anti-CD4 and anti-CD8 depleting antibodies. Consequently, mice were bled weekly to demonstrate the kinetics of T cell reconstitution following depletion (from d7 to d63).
Our results demonstrated that in healthy mice daily treatment with murine IL-7 significantly stimulated T cell proliferation and consequently increased cell number. This observation was further boosted by pre-complexing IL-7 with sCD127. For T cell depletion experiments, the kinetics of T-cell reconstitution was different between the CD4+ and CD8+ T cells. CD4+ T cell reconstitution was almost complete 6 weeks following T cell depletion, while CD8+ T cells were only partially reconstituted at this time point. Treatment with IL-7 or combined therapy had a transient and significant effect on T cell proliferation and reconstitution, and this influence was abrogated after treatment discontinuation. Interestingly, CD8+ T cells exert greater responses to our treatments in that a more pronounced proliferation and significant increase in cell number was observed relative to the effect seen on CD4+ T cells in both healthy and depleted mice.
In conclusion, antibody-mediated T cell depletion is a potentially valuable tool to investigate lymphopenia-induced proliferation and potential therapies thereof. This study suggests that combining sCD127 and IL-7 therapies enhances IL-7-mediated T cell proliferation, and provides important information for the potential therapeutic use of sCD127 and its impact on IL-7 function.
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Fergusson, Joannah R. "Mucosal associated invariant T cells and related CD161 expressing T lymphocytes." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:c5490bde-61c4-4715-bbf9-728ec9a8d51a.
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The C-type lectin CD161 is expressed by a large number of T lymphocytes, with approximately a quarter of both T cell receptor (TCR)αβ+ and TCRγδ+ T cells expressing this marker. Within CD8+ T cells, a large proportion of these are comprised of Mucosal Associated Invariant T (MAIT) cells, a novel innate-like lymphocyte subset characterised by expression of a semi-invariant TCR together with high levels of CD161 (CD161++). These cells display a phenotype reflective of type 17 CD4+ helper T cells (Th17), which are also hallmarked by CD161 expression. Both MAIT and Th17 cells arise from preprogrammed progenitors, identifiable within umbilical cord blood by expression of CD161. Thus, CD161 appears to identify cells of a pre-determined and distinct phenotype. Whether this reflects a common transcriptional programme, developmentally induced within these cells, and further whether this extends to other CD161 positive T cells, was examined here by mRNA microarray analysis. This analysis identified a shared transcriptional signature and common innate-like function of all CD161 expressing T lymphocytes, and independent of TCR expression or lineage. Furthermore, a population of CD8+ T lymphocytes expressing lower levels of CD161 which overlap phenotypically with CD161++CD8+ MAIT cells was identified by both mRNA microarray analysis and mass cytometry (CyTOF); the CD161+CD8+ T cell population. TCR repertoire analysis, flow cytometry and cell culture experiments were utilised to investigate the origin of this subset, and its phenotype and function in both health and disease investigated in depth. This revealed a pre-programmed, tissue-resident memory population with potent effector functions. Both CD161++ MAIT and CD161+CD8+ T cells expressed high levels of the drug efflux pump MDR1, previously described to confer drug resistance to certain malignant cells. The significance of expression of this pump was hence investigated to determine its potential affect on the success of a variety of clinical therapies.
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Parra, Eduardo. "Molecular basis for costimulation of human T lymphocytes." Lund : Lund University, 1998. http://books.google.com/books?id=SgFrAAAAMAAJ.
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Rivet, Catherine Aurelie. "Study of early signaling events in T cell activation enabled through a modular and multi-time point microfluidic device." Thesis, Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/31674.
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Thesis (M. S.)--Bioengineering, Georgia Institute of Technology, 2009.Committee Chair: Kemp, Melissa; Committee Member: Brand, Oliver; Committee Member: Lu, Hang. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Kurioka, Ayako. "Mucosal associated invariant T cells and CD161 expressing natural killer cells." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:f994e661-d241-4a1c-ac56-b6bea73346ac.
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Mucosal-associated invariant T (MAIT) cells are a population of innate-like lymphocytes within the gut, liver and blood, expressing a semi-invariant T cell receptor (TCR) and high levels of the C-type lectin-like receptor, CD161. These cells recognise a metabolite of the microbial riboflavin synthesis pathway, presented by the highly conserved Major Histocompatibility Complex (MHC) class I-related protein, MR1, and are critical for the control of bacterial infections. The factors regulating the broad effector functions of MAIT cells have not been fully investigated. Utilising a novel flow cytometric killing assay, MAIT cells were shown here to require the induction of a cytotoxic phenotype through bacterial stimulation to efficiently kill target cells. Further in depth phenotypic analysis highlighted a distinct non-cytotoxic subset of CD4+ MAIT cells, with an altered cytokine-producing capacity, enriched within lymphoid tissues. Investigation into the potential role of these cells in psoriatic diseases revealed that MAIT cells within the synovial fluid of psoriatic arthritis patients are potently activated with increased IL-17 production, their frequency correlating with measures of clinical activity. MAIT cells also have an innate-like responsiveness to cytokines, a feature originally attributed to Natural Killer (NK) cells. Microarray analysis and mass cytometry experiments demonstrated that CD161 marks immature NK cells that have retained this ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus (CMV)-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. Thus, CD161 marks cells with innate-effector functions both in T cells and NK cells.
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Dittmer, Marie. "Influence of regulatory T cells on oligodendrocyte lineage cells." Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725831.
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One of the greatest unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS). Uncovering the mechanisms that govern remyelination and developing novel treatments will prove highly beneficial to patients’ quality of life. Oligodendrocytes, the myelinating cells of the CNS, play a central role in remyelination and originate from oligodendrocyte progenitor cells (OPCs). It has been shown that cells of the adaptive immune system, particularly CD4+ T cells, promote remyelination in vivo however the contributions of distinct T cell subsets are currently not known. Based on previous observations by the group that depletion of regulatory T cells (Treg) impairs remyelination in vivo, we hypothesised that Treg enhance remyelination through a direct effect on oligodendrocyte lineage cells. To test this hypothesis, murine Treg were first activated and differentiated in vitro, in parallel with activation of non-polarised CD4+ T cell controls (NP), and media from these cultures were harvested. The effects of these conditioned media on OPC proliferation, survival and differentiation was investigated using in vitro models of murine mixed glial cells and pure OPCs. Neither Treg- nor NP-conditioned media had an effect on OPC proliferation and survival. However, Treg-conditioned media directly enhanced OPC differentiation in both mixed glial and pure OPC models, whereas NP-conditioned media did not. These findings suggest that Treg secrete a factor that directly enhances OPC differentiation. Confirming that the OPC differentiation-enhancing effect of Treg was indeed protein-mediated, we showed for the first time that Treg produce CCN3, a protein which is best known for its role in promoting angiogenesis. Upon treatment with a CCN3 antibody, CCN3-depletion or treatment with CCN3-/- Treg-conditioned media, the OPC differentiation-enhancing effect of Treg was abolished in mixed glial cultures. However, in pure OPC cultures there was no such effect of these three different loss of function approaches. This suggests Treg-derived CCN3 does not mediate the direct Treg-enhancing effect on OPC differentiation, but an additional indirect effect potentially mediated by other cell types present in mixed glial cultures. Pilot studies suggest, that the direct OPC differentiating effect of Treg may be partially mediated via JAK/STAT and MAPK signalling pathways. These studies uncover a novel, beneficial role of Treg in remyelination through the direct enhancement of OPC differentiation. We show that Treg have a direct differentiating effect on a CNS progenitor cell population, and therefore the potential to play an intrinsic role in regeneration, that is distinctly different from known immunomodulatory functions of Treg. This new knowledge could prove invaluable in the development of novel remyelination-enhancing therapies.
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Grero, Dhanya. "Cytotoxicity of Vγ9Vδ2 T cells towards Colon Cancer Cells." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-230976.
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Immunotherapies for cancer are widely studied at present. We are currently studying a specific form of “Vγ9Vδ2 T cells” found in the peripheral blood of healthy donors that can be used for the killing of HT-29 colon cancer cells. In order to determine the cytotoxicity of effectors, Vγ9Vδ2 T cells towards target cells, HT-29, it is important to first evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population, and next to determine the phenotypic characterization, their activity and cytotoxicity in the presence of target cells. A flow cytometry and bead based assay was developed to evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population. Peripheral Blood Mononuclear Cells (PBMCs) were surface stained with monoclonal antibodies (MoAbs) conjugated to fluorochromes that are cross reactive to cell surface markers such as CD3 (T Lymphocytes), γδ2 and were mixed with fluorophore beads. In these assays, no washes and centrifugation steps were performed after the cell surface staining and bead addition. The absolute cell counts were evaluated based on referencing a known concentration of beads. In addition, quantification assays were also performed to measure the cell and bead loss on surface staining that included washes and centrifugation steps and thus found a higher percentage loss of cells than beads. Immunophenotyping assays with four color staining were performed to monitor the phenotypic differentiation of effector cells based on cell surface markers CD27 and CD45RA. Only the naïve (CD27+CDRA+) and terminally differentiated effector memory (CD27-CD45RA+) were identified on the assays performed using Vγ9Vδ2 T cells of different donors. A flow cytometry based cytotoxicity (FCC) assay was completed to monitor the effector cell activity (CD69+) in the presence and absence of target cells and also the cytotoxicity was measured based on % specific lysis of target cells at four different effector to target (E:T) cell ratios. Only preliminary data were obtained for the FCC assay and the development is still in progress.
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Zheng, Biao. "Inductive interactions between antigen presenting cells and T cells." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314796.
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Kwong, Amelia. "Crosstalk Between T Cells, Dendritic Cells, Cytokines, and Chemokines." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146198.
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T cells that came into contact with mature and immature dendritic cells had an overall reduction in gene expression in IL10, IL12, IL23, ICOS, TGFB, TNFA, PD1, TBET, GATA3, FASL, PERF, FOXP3, and CTLA4. T cells stimulated with immature dendritic cells had the most consistent results in decreasing gene expression in all the genes tested. T cells in contact with mature dendritic cells had mostly a decrease in gene expression, but in IFNG and Granzyme there was an increase in gene expression. However, when adding additional stimuli such as interferon(IFN) or hydroxychloroquine (HCQ) gene expression increased in all of the markers except for TGFB, PERF, and IL12. This leads me to believe that crosstalk is occurring between dendritic cells and T cells. This crosstalk could direct the particular cells to perform specialized functions, which can explain the increase and decrease of the markers tested. In addition, interferon and hydroxychloroquine seems to hyper-stimulate most markers to create an up regulation of gene expression.
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Mühle, Kerstin. "Interaction of CD8+CD40L+ T cells with B cells." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19127.
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ZTLs vermitteln die Eliminierung von infizierten und entarteten Zellen durch Apoptose. Neuste Erkenntnisse unserer Gruppe haben gezeigt, dass eine Subpopulation der CD8+ T-Zellen, anstelle der zytotoxischen Marker das Oberflächenmolekül CD40L exprimiert. Die Expression von CD40L ist bislang als Schlüsselmolekül für die CD4+ T-Zell vermittelte Hilfe bekannt, welche durch Bindung an den CD40 Rezeptor auf anderen Immunzellen induziert wird. Das von den CD4+ T–Zellen ausgehende CD40L Signal ist besonders für die T-Zell abhängige B-Zell Aktivierung und die Bildung von Keimzentren essentiell, in denen B-Zellen heranreifen und hochaffine Antikörper produzieren um den Organismus vor eindringenden Erregern zu schützen. Aufgrund der CD40L-assoziierten Helferfunktion sollte in dieser Arbeit untersucht werden, welche Auswirkungen die Interaktion von CD8+CD40L+ T-Zellen mit B Zellen hat. In in vitro Studien konnte gezeigt werden, dass 50% der antigen-spezifischen CD8+ T-Zellen nach Aktivierung durch B-Zellen CD40L hochregulieren. Sowohl auf RNA- als auch auf Proteinebene induzierten CD8+CD40L+ T-Zellen einen B-Zell Phänotyp, der stark dem von CD4+ T-Zellen stimulierten B-Zellen ähnelte. In Infektionsversuchen mit dem B-Zell-trophen Virus MHV-68 konnte gezeigt werden, dass transgene Mäuse mit CD40L defizienten CD8+ T-Zellen im Vergleich zu Kontrolltieren eine signifikante Reduktion der Keimzentrums-B-Zellen in den Lymphknoten der oberen Halsregion aufweisen. Eine genauere Betrachtung des B-Zell Repertoires von IgG Gedächtniszellen ergab jedoch, dass die Sequenzen der IGHJ3 Genfamilie bevorzugt für die Modifikation der CDR3 Region in Mäusen mit CD40L defizienten CD8+ T-Zellen verwendet wird, die eine entscheidende Rolle bei der Antigenerkennung spielt. Zusammengefasst kann mit dieser Arbeit zum ersten Mal gezeigt werden, dass CD8+CD40L+ T-Zellen Helferfunktionen durch Unterstützung der B-Zell Aktivierung und Bildung von Keimzentren übernehmen können.CTLs are important for the elimination of infected and degenerated cells by inducing apoptosis of the target cells. Recently our group identified a sub-population of CD8+ T cells expressing CD40L instead of common CTL markers. To that date, transient CD40L expression on T cells has been only described as a function of activated CD4+ T cells, which displays this key molecule for CD4+ T cell mediated help by binding to the CD40 receptor on other immune cells. Particularly, CD40L signaling provided by CD4+ T cells is indispensable for T cell dependent B cell activation and GC responses, which generate B cells secreting high affinity antibodies that protect the host from invading pathogens. Due to its associated helper functions, this thesis aimed to dissect whether CD40L positive CD8+ T cells are restricted to cytotoxic killing or if this sub-population possesses similar properties as CD4+ T cells when interacting with B cells. In vitro co-culture experiments showed that 50% of murine antigen specific CD8+ T cells up-regulated CD40L upon activation by antigen presenting B cells. When compared to CD40L deficient CD8+ T cells, the interaction of CD8+ CD40L+ T cells induced remarkable changes in B cells on the RNA and protein level and triggered a B cell phenotype resembling that of B cells primed by CD4+ T cells. By the infection of mice with the B cell trophic virus MHV-68, it was found that E8IcrexCD40Lflox transgenic mice lacking CD40L only on matured CD8+ T cells, exhibited a significant decrease of GC B cells in superficial cervical lymph nodes at the acute state of infection compared to WT mice. A closer look into the memory B cell repertoire revealed a preferred usage of the murine IGHJ3 gene family that modifies the CDR3 and thus the recognition groove of the B cell antibody in E8IcrexCD40Lflox mice. In summary, this work provides sufficient evidence that CD8+ CD40L+ T cells adopt helper-like functions by supporting B cell activation and subsequent GC formation.
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Le, Gouge Kenz. "Modelling the T-cell repertoires of circulating T-cells and its application in cardiovascular diseases." Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS705.
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Les maladies cardio-vasculaires MCV représentent la première cause de mortalité en Europe, devant les différents cancers, et sont un enjeu actuel majeur de santé publique. Le système immunitaire est impliqué dans l’étiologie de ces maladies. Parmi les nombreux acteurs du système immunitaire, les lymphocytes T jouent un rôle prépondérant dans l’établissement de ces maladies, leur progression ou la réparation des tissus endommagés. Les lymphocytes T exercent leur fonction suite à leur activation déterminée par leur capacité à reconnaitre de manière spécifique des protéines, ou antigènes, soit exogènes, issues par exemple de pathogènes, allergènes, ou endogènes issues par exemple du renouvellement physiologique cellulaire ou de cellules tumorales. Cette reconnaissance est opérée par un récepteur particulier, appelé le TCR pour T-cell receptor. Contrairement à la majorité des gènes, le TCR est généré par un processus de recombinaison somatique aléatoire entre une centaine de gènes appartenant à trois grandes familles : V, pour Variable, D pour Diversité et J pour Jonction. Ce mécanisme, unique aux gènes codant pour les récepteurs spécifiques d’antigènes, a lieu dans le thymus, au cours du développement et de la différenciation des lymphocytes T et conduit à la production de plusieurs milliards de TCR différents chez un individu. Cette diversité forme le répertoire TCR et confère à chaque individu la capacité de reconnaitre tout antigène, exogène ou endogène, et de mettre en œuvre une réponse immunitaire. Ainsi, le répertoire TCR va être façonné tout au long de la vie d’un individu au gré des expositions variables et/ou successives à l’environnement antigénique auquel il se confronte. Dans le cadre de ma thèse, j’avais pour objectif d’évaluer quel pouvait être le lien entre la composition du répertoire TCR et sa dynamique avec le développement et la progression des maladies cardio-vasculaires. D’une part, j’ai évalué la fiabilité des technologies de séquençage permettant l’analyse fine de la composition du répertoire TCR au travers de la quantification des séquences de plusieurs milliers de TCR. Au cours de ces travaux, j’ai développé un outil de contrôle qualité qui m’a permis d’identifier un phénomène de contamination dépendant de la gamme de séquenceur utilisant la technologie d’amplification par exclusion, et de mettre au point un algorithme de détection et de décontamination de nos données. D’autre part, j’ai caractérisé le répertoire TCR dans différentes situations de MCV. Au travers d’une collaboration nationale, j’ai caractérisé le répertoire TCR circulant de cas pédiatriques du syndrome d’inflammation multiple survenus suite à la COVID-19. Cette étude a été fondamentale pour confirmer l’effet superantigène à distance d’une infection au Sars-CoV2, et de démontrer la pertinence des données de séquençage TCR en complément d’observations cliniques pour l’aide au diagnostic. Dans le cadre d’une collaboration internationale, nous avons eu accès à des prélèvements sanguins de patients ayant eu un infarctus du myocarde. L’objectif de mes travaux était d’identifier, à partir des TCR du sang de ces patients, un ensemble de TCR capables de prédire la réparation cardiaque chez ces patients. Ces travaux ont permis de démontrer la faisabilité d’une méthode d’identification d’une signature de TCR distinguant les bons des mauvais réparateurs. Enfin, dans une seconde cohorte de patients atteints d’infarctus, j’ai exploré la pertinence de l’analyse en réseau des TCR pour l’analyse de données de séquençage à faible couverture. Ces travaux ont permis de montrer que les signatures associées au pronostic de réparation cardiaques n’étaient pas liées à des TCR connus pour des spécificités cardiaques. Ensemble, ces résultats ont permis de mieux délimiter les possibilités que peuvent apporter le séquençage massif de TCR dans le contexte des maladies cardiovasculairesCardiovascular diseases (CVD) are the leading cause of mortality in Europe, surpassing various cancers, and are a major current public health concern. The immune system is involved in the aetiology of these diseases. Among the many components of the immune system, T lymphocytes play a predominant role in the development, progression, or tissue repair of CVD. T lymphocytes carry out their function following their activation, which is determined by their ability to specifically recognise proteins or antigens, whether they are exogenous, such as those from pathogens or allergens, or endogenous, such as those from physiological cell renewal or tumour cells. This recognition is mediated by a specific receptor called the TCR, which stands for T-cell receptor. Unlike most genes, the TCR is generated through a random somatic recombination process involving around a hundred genes belonging to three major families: V for Variable, D for Diversity, and J for Junction. This unique mechanism, particular to genes encoding antigen-specific receptors, takes place in the thymus during the development and differentiation of T lymphocytes and results in the production of several billion different TCRs in an individual. This diversity forms the TCR repertoire and provides each individual with the ability to recognize any antigen, whether exogenous or endogenous, and initiate an immune response. Therefore, the TCR repertoire is shaped throughout an individual's life depending on variable and successive exposures to the antigenic environment they encounter. In the context of my thesis, my goal was to assess the connection between the composition of the TCR repertoire and its dynamics with the development and progression of cardiovascular diseases. First, I evaluated the reliability of sequencing technologies that allow for a detailed analysis of the TCR repertoire's composition through the quantification of sequences from thousands of TCRs. During this work, I developed a quality control tool that enabled me to identify a contamination phenomenon related to the sequencing platform utilizing the exclusion amplification technology and devised an algorithm for data detection and decontamination. Furthermore, I characterized the TCR repertoire in different cardiovascular disease (MCV) situations. Through a national collaboration, I characterized the circulating TCR repertoire in paediatric cases of multisystem inflammatory syndrome following COVID-19. This study was fundamental in confirming the remote superantigen effect of a Sars-CoV2 infection and demonstrating the relevance of TCR sequencing data in addition to clinical observations for diagnostic assistance. In an international collaboration, we had access to blood samples from patients who had experienced a myocardial infarction. The aim of my work was to identify, from the TCRs in these patients' blood, a set of TCRs capable of predicting cardiac repair in these patients. These efforts demonstrated the feasibility of a method to identify a TCR signature distinguishing good from poor repairers. Finally, in a second cohort of myocardial infarction patients, I explored the relevance of network analysis of TCRs for low-coverage sequencing data. These studies showed that the signatures associated with cardiac repair prognosis were not linked to TCRs known for cardiac specificity. Collectively, these results have helped to better define the possibilities that massive TCR sequencing can offer in the context of cardiovascular diseases
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Murphy, Craig Antony. "Characterisation of T cells in rats that develop independently of the thymus : lymphocytes with potential regulatory roles /." Title page, abstract and contents only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phm9771.pdf.
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May, Kenneth F. "T cell costimulation in anti-tumor immunity and autoimmunity." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085004772.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xv, 178 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 May 20.
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Ebert, Lisa Michelle. "The regulation of chemokine receptor expression upon T lymphocyte activation." Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phe165.pdf.
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Rigby, Mark R. "R T 6: a Bifunctional Protein of Regulatory T Cells." eScholarship@UMMS, 1995. http://escholarship.umassmed.edu/gsbs_diss/283.
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The immune system is a complex network of cells and molecules that is a powerful and necessary defense mechanism to protect the host from pathogens. When this system is non-functional or dysregulated, the host is susceptible to takeover or attack against self, both with often lethal sequelae. Over the past century remarkable advances have been made in understanding how the immune system functions and how to manipulate this knowledge for human benefit. One strategy used to understand immune system function is to determine how the activity of immune system cells is modulated by the proteins these cells express on their surface.
One rat T cell surface protein which was originally identified with antibodies almost two decades ago is the rat T cell alloantigen, RT6. During the intervening time enormous progress has been made in understanding the function of RT6+ T cells in normal and abnormal immune responses. In addition, during this time the characterization of RT6 genes, proteins, and homologues has occurred. One characterization of RT6 that is enigmatically missing is the function of this molecule. With this information it would be possible to determine how this molecule modulates T cell function. Therefore this project set out to begin to functionally characterize RT6 proteins. Part 1 of this project set out to determine if cell-surface RT6 proteins, like some other T cell surface proteins, could mediate T cell activation. Part 2 of this project was based on the recent observation that RT6 is homologous to NAD-catabolizing enzymes, and it was investigated whether RT6 proteins have ADP-ribosyltransferase activity.
In Part 1 of this work it is demonstrated that cell-surface RT6 proteins are capable of delivering activation signals to T cells. Crosslinking cell-surface RT6 with antibodies potentiates the ability of PMA treated T cells to proliferate in response to the T cell growth factors IL-2 and/or IL-4. Crosslinking RT6 on these cells increases the surface expression of IL-2 receptors, suggesting that RT6-mediated signals selectively enhance growth factor receptor expression. This work also investigated the mechanism through which RT6 may deliver its signal. It is demonstrated that RT6 proteins are physically associated with five other proteins, including the src family tyrosine kinases p56lck and p60fyn. This work also suggests a novel mechanism to regulate T cell signaling by accessory molecules, since PKC activation causes qualitative and quantitative changes in the proteins physically associated with RT6. This work indicates that cell-surface RT6 is capable of delivering an accessory T cell activation signal. Therefore, RT6 proteins may be involved in vivo with the activation and proliferation of RT6+ T cells.
Previous work in another laboratory has demonstrated that the RT6.2 protein possesses NAD glycohydrolase activity and indicated that RT6 proteins share overall sequence homology with ADP-ribosyltransferases. In Part 2 of this work, RT6 proteins are shown to possess NAD:arginine ADP-ribosyltransferase activity. ADP-ribosylation of proteins is a modification known to affect cell signaling and function. It is further demonstrated in this work that the substrate for RT6, extracellular NAD, inhibits T cell proliferation in a dose- and stimulus-dependent manner. Taken together, these studies suggest that through their enzymatic activities RT6 proteins modulate T cell activity.
This work is the first to demonstrate that RT6 has two, possibly separate, functional characteristics. RT6 can therefore be described as a bifunctional T cell surface protein. RT6+ T cells play critical roles in regulating immune system responses in health and disease. Because of these functional studies on RT6 proteins, it can now be investigated how RT6 proteins may modulate T cell responses in different immunological situations. Thus, this work will provide the foundation to determine if and how RT6 proteins modulate immune system function in health and disease.
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Smits, Hermelijn Hélène. "Instruction of effector T cell programs by flexible dendritic cells." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/86946.
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