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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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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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Im, Jin Seon. "Molecular characterization of T cell receptors and non-MHC restricted T cell receptor binding peptides." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/284969.
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T cells recognize antigenic peptides presented by MHC molecules on antigen presenting cells (APC) through T cell receptors (TCRs). Since TCRs are very similar to antibodies in structure and genetics, TCRs might have the potential to bind free antigens as antibodies do. Here, peptides which bound TCRs irrespective of MHC molecules have been identified by screening "one-bead one-peptide" combinatorial libraries. Peptides: VRENAR, RTGNYV, GKMHFK, KDAVKR and RKPQAI bound recombinant Jurkat single chain T cell receptors (scTcrs). GKMHFK, KDAVKR and RKPQAI were also specific for natural TCRs on the Jurkat cell surface. Molecular modeling implies that Glu96 in the CDR3 loop of TCR alpha chain is a candidate for the peptide interaction site. However, TCR-binding peptides did not induce biological effects on parental Jurkat cells. To extend this study to a biologically relevant system, diabetogenic T cells involved in insulin-dependent diabetes mellitus (IDDM) have been characterized. GAD(524-543) responding T cells showed restricted TCR variable gene usage, which utilized preferentially Vα17 and Vβ12. Three domain single chain T cell receptors (3D scTcr) were constructed as tools to investigate potential therapies for IDDM and to identify peptides which bind to TCR without association of MHC molecules. Functional analysis has demonstrated that GAD(524-543)-specific scTcrs retained the ability to bind GAD(524-543)/IAg7 complex. This work shows that recombinant scTcrs can bind cognate peptide presented by MHC molecules, therefore they can be used as substitutes for natural TCRs in screening "one-bead one-peptide" combinatorial libraries to identify TCR-binding peptide.
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Jiang, Ning. "Kinetic analysis of Fcγ receptor and T cell receptor interacting with respective ligands." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/26716.
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Low affinity Fcg receptor III (FcgRIII, CD16) triggers a variety of cellular events upon binding to the Fc portion of IgG. A real-time flow cytometry method was developed to measure the affinity and kinetics of such low affinity receptor/ligand interactions, which was shown as an easily operated yet powerful tool. Results revealed an unusual temperature dependence of reverse rate of CD16aTM dissociating from IgG. Except for a few studies using mammalian cell CD16s, most kinetics analyses use purified aglycosylated extracellular portion of the molecules, making it impossible to assess the importance of the receptor anchor and glycosylation on ligand binding. We used a micropipette adhesion frequency assay to demonstrate that the anchor length affects the forward rate and affinity of CD16s for IgG in a species specific manner, most likely through conformational changes. Receptor glycosylation dramatically reduced ligand binding by 100 folds. T cell receptor (TCR) is arguably the most important receptor in the adaptive human immune system. Together with coreceptor CD4 or CD8, TCR can discriminate different antigen peptides complexed with major histocompatibility complex (MHC) molecule (pMHC), which differ by as few as only one amino acid, and trigger different T cell responses. When T cell signaling was suppressed, TCR had similar affinity and kinetics for agonist and antagonist pMHC whose binding to CD8 was undetectable. TCR on activated T cell had a higher affinity for pMHCs, suggesting that TCRs organize themselves differently on activated T cells than on naïve T cells. In the absence of inhibitors for signaling, TCR binds agonist pMHC with several orders of magnitude higher affinity than antagonist pMHC. In addition, engagement of TCR by pMHC signals an upregulation of CD8 binding to pMHC, which is much stronger than the TCR-pMHC binding. The transition from weak TCR binding to the strong CD8 binding takes place around 0.75 second after TCR in contact with pMHC and can be reduced by several inhibitors of tyrosine and lipid phosphorylation, membrane rafts, and actin cytoskeleton. These results provide new insights to understanding T cell discrimination.
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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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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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Li, Xiaoying. "T cell receptor repertoires of immunodominant CD8 T cell responses to Theileria parva." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/19552.
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Previous research has provided evidence that CD8 T cells mediate immunity against infection with Theileria parva. However, the immunity induced by one parasite strain doesn‟t give complete protection against other strains and this is associated with parasite strain specificity of the CD8 T cell responses. There is evidence that such strain specificity is a consequence of the CD8 T cell responses of individual animals being focused on a limited number of immunodominant polymorphic peptide-MHC determinants. Dominant responses to the Tp2 antigen have been demonstrated in animals homozygous for the A10 MHC haplotype. Three Tp2 epitopes recognised by A10+ animals (Tp249-59, Tp250-59 and Tp298-106) have been defined. This project set out to investigate the dominance of these epitopes and to examine the T cell receptor (TCR) repertoires of the responding T cells. The specific objectives were to: (i) Determine the dominance hierarchies of the three defined Tp2 epitopes in both A10-homozygous and -heterozygous cattle. (ii) Examine the clonal repertoires of epitope-specific responses by analysis of TCR gene expression. (iii) Isolate full-length cDNAs encoding TCR α and β chain pairs from T cell clones of defined epitope specificity and use them to generate cells expressing the functional TCRs. Using MHC class I tetramers the relative dominance of CD8 T cell responses were found to differ between A10-homozygous and heterozygous cattle. All A10-homozygous cattle examined had detectable responses to all 3 Tp2 epitopes, the Tp249-59 epitope consistently being the most dominant. By contrast, only some A10-heterozygous cattle had detectable responses to Tp2 and when present the response was specific only for the Tp298-106 epitope. Analyses of the sequences of expressed TCR β chains showed that the responses in individual animals were clonotypically diverse, but often contained a few large expanded clonotypes. The TCRs of Tp298-106–specific T cells showed preferential usage of the Vβ13.5 gene and the frequent presence of a “LGG” motif within the CDR3 of the B chain. A conserved (public) TCRβ clonotype shared by the Tp250-59-specific CD8 T cells from all A10-homozygous cattle was identified. The TCRα chains co-expressed with this public TCRβ clonotype were identified for a number of T cell clones. Lentivirus transduction of Jurkat cells with three full-length TCR α and β chain pairs resulted in successful expression of one of the α/β chain pairs as a functional TCR, thus providing the basis for future work to generate bovine T cells expressing defined TCRs in vitro.
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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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Moody, Anne Marie. "T-cell receptor studies in myasthenia gravis." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337448.
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Palmer, M. S. "Studies on the murine T-cell receptor." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379915.
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Downs, Anne-Marie. "Functional analysis of T-cell receptor gene transduced T-lymphocytes." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429389.
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Zarozinski, Christopher C. "T Cell Receptor-Dependent and Independent Events During Potent Anti-Viral T Cell Responses." eScholarship@UMMS, 1998. http://escholarship.umassmed.edu/gsbs_diss/175.
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The relative contribution of T cell receptor-dependent stimulation versus TcR-independent bystander stimulation in the massive increase in the number of activated proliferating CD8+ T cells seen during acute many acute viral infections is unclear. To determine if this increase was the result of TcR-independent bystander activation and proliferation, anti-viral cytotoxic T lymphocytes were induced in vivo via DNA immunization so that the anti-viral immune response could be examined in the absence of the high levels of cytokines generated during acute infection. After a single immunization with a plasmid encoding the nucleoprotein of the lymphocytic choriomeningitis virus (LCMV) a nearly 2 log10 reduction in viral titers in the spleen was observed 3 days after LCMV infection. After 2 or 3 immunizations a greater that 3 log10 inhibition of viral titers in the spleen was observed, with most animals having no detectable virus. After intracerebral challenge vaccinated animals displayed either protection or enhanced immunopathology leading to accelerated kinetics of death. By limiting dilution analysis LCMV-specific CTL precursors were detected in both the spleen and lymph nodes of vaccinated animals. C57BL/6 mice inoculated with DNA demonstrated an anamnestic CTL response detectable at days 4 after LCMV challenge. However, the numbers of CTL precursors elicited by DNA vaccination was too low to determine if cytokine-mediated TcR-independent bystander activation and proliferation had taken place.
HY-specific TcR-transgenic mice, which have a restricted TcR repertoire, and LCMV-carrier mice, which are tolerant to LCMV, were used to determine the extent of TcR-independent bystander activation and proliferation during acute LCMV infection. LCMV infection of C57BL/6 mice induced CTL that lysed uninfected H-2k and H-2d allogeneic targets, but, LCMV-induced CTL from HY- transgenic mice lysed only the H-2k-expressing cells. The HY-mice generated both anti-H-2k and anti-H-2d CTL in mixed lymphocyte cultures, strongly suggesting that the generation of allospecific CTL during acute LCMV-infection is antigen specific. During the LCMV infection there was blastogenesis of the CDB+ T cell population, but the HY-specific T cells remained small in size, and did not alter their expression of the activation molecules CD44 and MEL-14. In order to examine the potential for bystander stimulation under conditions of a very strong CTL response, T cell chimeras were made between normal and HY-transgenic mice. Even in the context of a normal vicus-induced CTL response, no stimulation of HY -specific T cells was observed, and HY-specific cells were diluted in number by day 9 post-infection. In LCMV-carrier mice in which donor and host T cells could be distinguished by Thy 1 allotypic markers, adoptive transfer of LCMV-immune T cells into LCMV-carrier mice, whose T cells were tolerant to LCMV, resulted in activation and proliferation of donor CDB cells but little or no activation of host CDB+ T cells. These results show that TcR-independent bystander activation of non virus-specific T cells is not a significant component of an anti-viral T cell response and support the hypothesis that the massive polyclonal CTL response to LCMV infection is virus-specific.
T cells activated during potent anti-viral immune responses are sensitized to undergo apoptosis after strong TcR-stimulation in a process known as activation-induced cell death (AICD). To determine if T cells, not participating in the immune response were also subject to AICD, LCMV-carrier mice were used. Using TUNEL flow cytometry, it was shown that after reconstitution of Thy 1.2+ LCMV-carrier mice with spleen cells from Thy 1.1+ LCMV-immune mice, the Thy 1.2+ host T cells which were not specific for the virus and did not proliferate in a bystander fashion, were rendered sensitive to TcR-induced apoptosis in vitro. This bystander sensitization to AICD was shown not to be dependent on the continued presence of activated proliferating donor cells during the in vitro culture period. Bystander sensitization to AICD was not the result of an antigen presenting cell defect, but rather was the result of an in vivo conditioning of the T cells themselves. The mechanism of this sensitization was, at least, partially dependent on the ability of host T cells to respond to IFNγ, and on the expression of Fas ligand on the activated, proliferating donor cells. This bystander sensitization to AICD may explain why memory T cell responses are so poor during acute viral infection and can serve as a potential mechanism for virus-induced immunosuppression.
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Tibbitt, Christopher Andrew. "The role of T cell receptor signal intensity in T helper 17 cell development." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2885.
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T-helper (Th) 17 cells are a subset of CD4+ T cells defined through the release of the cytokine interleukin-17a (IL-17a). Activation of these cells is critical for protection against some extracellular bacterial and fungal pathogens. However, a dysregulated Th17 response targeted against self is thought to play an important role in the immunopathology of a number of autoimmune conditions including Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS) or inflammatory arthritides. Further understanding of the mechanisms that influence the development of Th17 cells may aid future therapeutic targeting of these cells. Whilst the role of the cytokine milieu in Th cell polarisation is relatively well characterised, the degree of signalling through the TCR can also shape the form of the Th cell response. Both the density of antigenic peptide available and the affinity of the antigenic peptide for a particular TCR can contribute to the degree of TCR signalling. The hypothesis of this project was that TCR signal intensity could alter the development of Th17 cells from a naive precursor population. In particular, it was of interest to determine how citrullination of a putative TCR contact amino acid in an antigenic peptide could alter the Th cell response observed. The 5/4E8 T-cell receptor transgenic (TCR Tg) mouse provides a model in which >80% of T-cells specifically recognise an immunodominant epitope derived from the G1 domain of aggrecan – peptide-84-103 (p84-103). This model allowed for the examination of these factors and the underlying mechanism ex vivo using a purified naive CD4+ T cell population in coculture with LPS-matured dendritic cells (mDCs). The data presented in this thesis show the activation, proliferation and effector responses of naive 5/4E8 TCR Tg T cells to alterations in both cognate peptide (p89- 103) density and affinity through citrullination of a putative TCR contact residue (R93Cit). Interestingly, by reducing TCR signal strength the observed response shifts from one dominated by the Th2 phenotype to Th17 cells. Linking the degree of TCR activation to Th cell phenotype was the intensity of IL-2 signalling that in turn shaped the balance between phosphorylated STAT3 and STAT5. Compared to p89-103-primed T cells, T cells responding to R93Cit produced less IL-2, expressed lower levels of the ILiii 2 receptor subunit CD25, and showed reduced levels of STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL-2 blockade in p89-103-primed T-cells selectively reduced STAT5 but not STAT3 phosphorylation, and concomitantly enhanced Th17 development. In summary, this work indicates the impact that changes to the intensity of TCR signalling can have on the murine Th17 response. Indeed, these data illustrate how a disease-relevant post-translational modification such as citrullination can promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells.
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Tubb, Vanessa. "The development of novel T cell receptor, and chimeric antigen receptor, engineered T cell therapies for the treatment of cancer." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7725/.
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The ability to generate a tumour-reactive T cell compartment is possible through the genetic engineering of patient T cells with tumour-reactive TCRs or CARs. The clinical testing of such therapies is garnering increasingly encouraging results, particularly in haematological malignancies. However, identification of more potent and specific target antigens, and combating immunosuppression in the tumour microenvironment is necessary to transfer these clinical responses to solid tumours. We investigated whether recurrent cancer mutations encode immunogenic neoantigens presented by common HLA class I alleles. We isolated TCRs specific for putative neoepitopes derived from common mutations in calreticulin (mCALR), and FBXW7. These TCRs showed moderate affinity but fine peptide specificity for mutant peptides, with some TCRs capable of recognising mutant cell lines. However, mass spectral analysis of MHC-eluted peptides and MHC class I tetramer staining of patient T cells suggested putative mCALR neoepitopes were not naturally processed and presented. Finally, we investigated whether ectopic expression of arginine recycling enzymes argininosuccinate synthetase (ASS) and/or ornithine transcarbamylase (OTC) in CAR T cells endows resistance to immunosuppression driven by arginine depletion. Increased ASS/OTC expression and function was detected in CAR-engineered T cells, however enhanced cytotoxicity and proliferation of CAR T cells was not observed following arginine depletion.
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Okkenhaug, Klaus. "Signalling through the T cell costimulatory receptor CD28." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq41262.pdf.
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Vessey, S. J. R. "A molecular analysis of the T-cell receptor." Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:87b560f9-b1d6-4b12-9c94-fd1b4de397f6.
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The recognition of MHC-peptide ligands by the T cell receptor (TCR) is central to the induction of the adaptive immune response. This thesis describes the development of a bioassay for TCR recognition which was then used to undertake a molecular analysis of the TCR/MHC-peptide interaction. 1. A TCR-CD3ϛ chimeric receptor was stably expressed in the cell line RBL-2H3 to give the transfectant RBL-008. RBL-008 was shown to exhibit MHC-restricted peptide-specific responses to both cellular and multimerised recombinant HLA-A2-pol peptide targets (Chapter 3). 2. By competitively inhibiting the response of RBL-008 to HLAA2 pol complexes with monovalent soluble recombinant MHCpeptide complexes it was confirmed that the TCR makes significant contact with both the MHC and peptide parts of its ligand. Furthermore it was found that only a few peptides in a random mixture can prevent contact between the TCR and HLA-A2. This has implications for positive selection since it supports evidence suggesting that some TCRs can be selected on a wide range of unrelated peptides (Chapter 4). 2. The bioassay was used to examine the flexibility of TCRpeptide interactions using a panel of variant peptides designed on the basis of the previously published HLA-A2-pol peptide structure (Chapter 5). Several variant peptides were recognised by the TCR and interestingly one of these altered peptide ligands was actually recognised better than the index peptide, raising the prospect of designing 'improved epitopes'. 3. By mutating the β chain of TCR-CD3ϛ chimeric receptor it was shown that allelic variation in the TCR genes can have a significant effect on antigen recognition and may therefore be disease susceptibility candidates genes (Chapter 6). 4. The structural relationship between the V and C domains of the TCR was examined and found to be of considerable functional significance since disruption of this relationship resulted in loss of expression of the TCR-CD3ϛ receptor.
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Fernandes, Ricardo A. "Controls on T-cell receptor phosphorylation and triggering." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:f0933a44-e1d6-4941-a541-c0cf903532ca.
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An effective immune response in mammalian cells relies on a network of molecular interactions to detect and respond to pathogens. The T-cell receptor (TCR) is one of the most important components of this system responsible for the outcome of the immunological response. Paramount to its role is its ability to efficiently signal a productive interaction with a peptide embedded in an MHC molecule. Important aspects of TCR structure and organization are unknown, limiting the current understanding of this process and rendering it highly controversial. The work described in this thesis seeks to define the valency, structural organization and signalling properties of the TCR in order to provide a better framework for thinking about the receptor-triggering problem. The results suggest that a largely monovalent complex diffuses at the surface of T cells, which is able to trigger intracellular signalling in the absence of large structural rearrangements of the extracellular subunits of the TCR. Moreover, a recently proposed mechanism involving conformational rearrangements of the cytoplasmic domains of the complex is shown to fail to explain the regulation of TCR phosphorylation. Steps are also taken toward investigating the role of more subtle conformational rearrangements at atomic resolution. Finally, an investigation of what controls tyrosine phosphorylation of the receptor in resting T lymphocytes led to the development of new approaches to address the role of specific phosphatases. The outcome of this analysis suggested how a finely-tuned balance between kinase and phosphatase activity, at both global and local levels, regulates TCR phosphorylation and T-cell activation.
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Mukhopadhyay, Himadri. "Multisite phosphorylation in T cell receptor proximal signalling." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:25bd3d44-34eb-46d7-8ce8-fec2eb13b75b.
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T cell receptor proximal signalling represents a specific instance of a multisite phosphorylation system. Receptor phosphorylation is regulated by the opposing actions of the kinase LCK, and phosphatases such as CD45 and CD148. Particular phosphoforms recruit the kinase ZAP-70, which once bound, propagates downstream signalling. In this thesis we investigate the functional consequences of multiple phosphorylation sites on the dose-response profiles of receptor phosphorylation. We combine mathematical modelling with cellular reconstitution to assess the effect of multiple modification sites on the potency and sensitivity of receptor phosphorylation. We find that multiple sites enhance the potency of receptor phosphorylation, but do not alter the sensitivity of dose-response profiles. This correlation between the number of sites and response potency is consistent with a mechanism whereby phosphorylation mediates an enhancement in the enzymatic efficiencies of modification.
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Trop, Sebastien. "Regulation of T cell development by the pre-T cell receptor and the CD45 phosphatase." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37622.
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A molecular interplay between the signaling components utilized by cytokine receptors, the pre-T cell receptor (pre-TCR), and the T cell receptor (TCR) is presumed to be required for proper regulation of thymocyte development. The earliest intrathymic progenitors are known to depend on cytokine signaling. However, the mechanisms regulating cytokine signaling during thymopoiesis have not been characterized. Moreover, the contribution of cytokine signaling to the maturation of CD4-CD8- thymocytes into CD4+CD8+ thymocytes, mainly controlled by the pre-TCR, is uncertain. Overexpression of SOCS-1, a negative regulator of cytokine signaling, in developing thymocytes resulted in decreased proliferation following pre-TCR signaling, revealing a novel role for cytokine signaling at this developmental stage. Moreover, pre-TCR signaling negatively regulates SOCS-1 expression, establishing a link between the pre-TCR and mechanisms regulating cytokine signaling. During the later stages of thymocyte development, signals delivered by the pre-TCR and TCR assume a dominant regulatory role. Although structurally similar to the TCR, the pre-TCR possesses distinct biological properties. The major difference between these receptors is the presence of the pTalpha chain in the pre-TCR, which is structurally different from the TCRalpha chain present in the TCR. The connecting peptide domain of pTalpha regulates the interaction between the pre-TCR and the TCR&zgr; subunit. In addition, the structural differences between pTalpha and TCRalpha constitute a post-translational regulatory mechanism to prevent the coexpression of pre-TCR and TCR at the cell surface of CD4+CD8+ thymocytes, as pTalpha cannot pair with TCRbeta in the presence of TCRalpha. The competitive advantage of TCRalpha relates to the position of the bridging cysteine residue within its connecting peptide domain. Thus, the structural features of pTalpha regulate the assembly and surface expression of the pre-TCR, and endow it
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Thomas, N. C. "Computational approaches to the study of T cell migration and the T cell receptor repertoire." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1426946/.
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Two pertinent questions in T cell immunology are addressed by using techniques from machine learning to describe T cell migration dynamics and characteristics of the T cell receptor repertoire. Naive T lymphocytes exhibit extensive antigen-independent recirculation between blood and lymph nodes, where they may encounter dendritic cells carrying cognate antigen. The time T cells may spend in an individual lymph node is estimated by analysing data from long term cannulation of blood and efferent lymphatics of a single lymph node in sheep. The distribution of transit times of migrating T cells is determined empirically by applying the Least Absolute Shrinkage & Selection Operator to experimental data. The results demonstrate that the rapid recirculation of lymphocytes observed at a macro level is compatible with predominantly randomised movement within lymph nodes. High throughput sequencing provides an opportunity to analyse the repertoire of antigen specific receptors with an unprecedented breadth and depth. However, the quantity of raw data produced by this technology requires efficient ways to categorise and store the output for subsequent analysis. A novel application of a finite state automaton is implemented to characterise T cell receptor sequences for the purpose of downstream analysis. Finally, the clonal theory of adaptive immunity proposes that immunological responses are encoded by increases in the frequency of lymphocytes carrying antigen-specific receptors. Both unsupervised (hierarchical clustering) and supervised (support vector machine) learning techniques are successfully used to track changes in the T cell receptor repertoire induced by immunization, using contiguous stretches of amino acids within the T cell receptor complementarity determining region 3 repertoire of different mice.
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Stevens, C. N. "The interferon alpha receptor utilises T-cell receptor-associated proteins for signalling." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/15852/.
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The interferon alpha receptor (IFNAR) and T-cell receptor (TCR) are expressed upon the T-cell surface. The dimeric Class I interferon receptor is a cytokine receptor that recognises interferons such as IFNα. Interferons (IFNs) are pluripotent, antiviral cytokines that causes antiproliferative effects, primarily through Jak/STAT signalling. The T-cell receptor is an antigenic receptor that recognises antigenically-derived peptides in the context of the MHC complex located on an antigen presenting cell, resulting in a cellular proliferation. Although both receptors elicit opposing cellular outcomes, both the TCR and IFNAR activate the ERK MAPK signalling pathway, albeit with a different time course. Furthermore, studies have shown that the IFNAR and TCR utilise an overlapping subset of proteins for this pathway to occur such as CD45, Lck and Zap70. In this study evidence is presented to show that two further TCR-associated proteins are phosphorylated in response to the IFNAR; the 95kDa guanosine nucleotide exchange factor, Vav, and the 76kDa adaptor protein Slp76. This proceeds in a similar manner to that observed at the TCR. Furthermore, the absence of either protein impairs IFNAR-induced ERK MAPK signalling. The similarities between TCR and IFNAR signalling led to questioning of whether crosstalk occurs between the two receptors. To address this possibility a TCRβ deficient cell line, which lacks functional TCR expression, was utilised. It was demonstrated that the absence of the TCR completely abrogates the ERK MAPK response emanating from the IFNAR yet Jak/STAT signalling is unaffected. These results highlight for the first time an intimate connection between the TCR and IFNAR.
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Maciocia, P. M. "Targeting the T-cell receptor beta constant region for investigation and immunotherapy of T-cell malignancies." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1551063/.
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T-cell lymphomas and leukemias are aggressive, treatment-resistant cancers with poor prognosis. Immunotherapeutic approaches have been limited by a lack of target antigens discriminating malignant from healthy cells. While treatment of B-cell cancers has been enhanced by targeting pan B-cell antigens, an equivalent approach is not possible for T-cell malignancies since profound T-cell depletion, unlike B-cell depletion, would be prohibitively toxic. We propose an immunotherapeutic strategy for targeting a pan T-cell antigen without causing severe depletion of normal T-cells. The α/β T-cell receptor (TCR) is a pan T-cell antigen, expressed on >90% of T-cell lymphomas and all normal T-cells. An overlooked feature of the TCR is that the β-constant region comprises 2 functionally identical genes: TRBC1 and TRBC2. Each T-cell expresses only one of these. Hence, normal T-cells will be a mixture of individual cells expressing either TRBC1 or 2, while a clonal T-cell cancer will express TRBC1 or 2 in its entirety. Despite almost identical amino acid sequences, we identified an antibody with unique TRBC1 specificity. Flow cytometry (FACS) of T-cells in normal donors (n = 27) and patients with T-cell cancers (n = 18) revealed all subjects had TRBC1 and 2 cells in both CD4 and CD8 compartments, with median TRBC1 expression of 35% (range 25-47%). In addition, we examined viral-specific T-cells in healthy volunteers, by generation of Epstein Barr virus-specific primary cytotoxic T-cell lines (3 donors) or by identification of cytomegalovirus- (3 donors) or adenovirus- (5 donors) specific T-cells by peptide stimulation. We demonstrated similar TRBC1: 2 ratios in viral-specific cells, suggesting that depletion of either subset would not remove viral immunity. Next, using FACS and immunohistochemistry, we showed that TCR+ cell lines (n = 8) and primary T-cell lymphomas and leukemias (n = 55) across a wide range of histological subtypes were entirely restricted to one compartment (34% TRBC1). As proof of concept for TRBC-selective therapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T-cells. After retroviral transduction of healthy donor T-cells, comprising mixed TRBC1/2 populations, 90% of T-cells expressed CAR on the cell surface. No detectable TRBC1 T-cells remained in the culture, suggesting selective depletion of this population. Anti-TRBC1 CAR T-cells secreted interferon-γ in response to TRBC1-expressing target cell lines (p < 0.001) or autologous normal TRBC1+ cells (p < 0.001), and not TRBC2 cell lines or autologous normal TRBC2 cells. Anti-TRBC1 CAR killed multiple TRBC1 cell lines (p < 0.001) and autologous normal TRBC1cells (p < 0.001), and not TRBC2 cell lines or autologous normal TRBC2 cells. These cell-line based findings were confirmed using primary cells from two patients with TRBC1+ adult T-cell leukaemia/lymphoma. We demonstrated specific tumour kill by allogeneic or autologous T-cells in vitro, despite partial downregulation of surface TCR by tumour cells. We developed a xenograft murine model of disseminated T-cell leukemia by engrafting engineered firefly luciferase+ TRBC1+ Jurkat cells in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Bioluminescent imaging and FACS of marrow at 5 days following IV T-cell injection showed that mice treated with anti-TRBC1 CAR T-cells and not non-transduced (NT) T-cells had disease clearance (p < 0.0001). In a further model, mice were engrafted with equal proportions of TRBC1-Jurkat and TRBC2-Jurkat cells. FACS analysis of bone marrow at 5 days post T-cells demonstrated specific eradication of TRBC1 and not TRBC2 tumour by anti-TRBC1 CAR (p < 0.001). In summary, we have demonstrated a novel approach to investigation and targeting of T-cell malignancies by distinguishing between two possible TCR β-chain constant regions. Using CART-cells targeting TRBC1 we have demonstrated proof of concept. Unlike non-selective approaches targeting the entire T-cell population, TRBC targeting could eradicate a T-cell tumour while preserving sufficient normal T-cells to maintain cellular immunity.
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Blish, Catherine Anne. "Modulation of T cell function and T cell receptor repertoire during the induction of peripheral tolerance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8323.
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Malik, Amna. "Anti-CMV CD8+ T-cell epitope specificities and T-cell receptor repertoires in African study subjects." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:25b09543-3d8b-4340-a003-8ebe7827ee21.
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This work focuses on chronic viral infection in populations in sub-Saharan Africa. Although some of these viruses are endemic, there is a paucity of data charac- terising the immune responses in the relevant populations affected. The primary focus of this thesis is cytomegalovirus (CMV). Almost 90% of children in Africa are infected by the age of 12 months. A strong virus-specific immune response controls but does not clear CMV infection, and CMV typically remains latent; how- ever, reactivation is possible, particularly in the context of HIV infection and other states of immunosuppression. The high-frequency, immunodominant CD8+ T-cell responses, the CMV epitopes targeted, and the T-cell receptor repertoires underly- ing these responses have not previously been well defined in African populations. Furthermore, it is not known how the T-cell repertoire changes over the course of infection in response to CMV. To gain a better understanding of these aspects of CMV infection and immunity, I defined the immunodominant CMV-specific CD8+ T-cell responses within a cohort of sub-Saharan African study subjects (Chapter 3). Using next-generation sequencing of the CMV-specific CD8+ T-cell receptor (TCR) repertoire, focusing on a single immunodominant HLA-B*44:03-restricted response, I studied TCR repertoire bias (Chapter 4) and the changes in the TCR repertoire within children and adults followed longitudinally over 10 years (Chapter 5). Two other viruses, human Parvovirus 4 (PARV4) and Hepatitis B virus (HBV) are also endemic in these populations, may, like CMV, also be of particular signifi- cance in the setting of HIV co-infection, but are under-represented in the literature for Africa. I present data that I contributed to projects setting out to improve our understanding of the local epidemiology of these infections and to characterise relevant CD8+ T-cell responses (Chapter 6). Together, this work contributes to- wards a better understanding of immune responses that control chronic infections prevalent in African populations.
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Sandalova, Elena. "Regulation of the pro-apoptotic protein bim by T cell receptor triggering in human T cells /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-041-1/.
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Gohil, Satyen Harish. "Pre-clinical development of novel ROR1 chimeric antigen receptor T cells and bispecific T cell engagers." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042372/.
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Receptor tyrosine kinase like orphan receptor 1 (ROR1) is an onco-embryonic antigen present on a range of solid and haematological malignancies, including chronic lymphocytic leukaemia. Additionally, limited, low level expression on normal tissues makes it an attractive therapeutic target. Chimeric antigen receptor T cells and Bispecific T Cell Engagers have emerged as exciting immunotherapeutic approaches, utilising the inherent cytotoxic potential of autologous T cells to yield demonstrable benefit for patients. We therefore aimed to generate novel ROR1 CAR T cells and BiTEs. Following a rat ROR1 immunisation programme, we screened over 150 single cell hybridoma clones to isolate 13 novel antibodies of which 10 bound in a single chain variable fragment format. Iterative optimisation led to two lead candidates that imparted superior cytotoxicity and cytokine secretion. To minimise immunogenicity we screened 50 humanised ROR1 scFv variants and selected a final humanised candidate, hF(1x1), which maintained effector function, specificity and demonstrated broad applicability against a panel of cell lines representing various tumour subtypes. Focusing specifically on haematological cell lines and CLL, our humanised CAR demonstrates superior cytotoxicity compared to previously reported ROR1 constructs. However, low ROR1 antigen density limits efficacy in B cell malignancies, compared to CD19 CAR T cells and strategies to overcome this are in development. Our ROR1 BiTE mediates cytotoxicity at low concentrations (ng/ml) and effector to target ratios against cell lines, but in untreated and relapsed CLL patients, inherent T cell dysfunction limits efficacy. This can be overcome with the BTK inhibitor Ibrutinib, with T cells isolated from patients on treatment, showing markedly improved cytotoxicity against autologous CLL cells. This work has laid the preclinical foundations for translation of these novel agents into clinical trials for a range of tumours including CLL and many of which have high unmet therapeutic need.
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Uttenthal, B. J. "T cell receptor-transduced regulatory T cells : functional studies in models of graft-versus-host disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1379030/.
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Alloreactive immune responses directed against malignant cells in recipients of allogeneic haematopoietic stem cell transplants are able to cure patients with haematological cancers. However, such immune responses may cause severe morbidity when directed against healthy recipient tissue, resulting in graft-versus-host disease (GvHD). Naturally occurring regulatory T cells (Tregs) are CD4+ T cells characterized by their expression of the transcription factor Foxp3. Whilst adoptively transferred polyclonal Tregs suppress GvHD in several murine models, their lack of specificity may compromise beneficial immunity against malignancy or infection. The generation of MHC class I-restricted, alloantigen-specific Tregs would allow them to recognize antigen presented directly on GvHD target tissues, concentrating their sites of activation at these tissues and potentially reducing non-specific immune suppression. I have generated ‘converted’ Tregs through retroviral transfer of genes encoding Foxp3 and specific MHC class I-restricted T cell receptors (TCRs) into conventional CD4+ T cells. I used the 2C-TCR, which recognizes the MHC class I molecule H-2Ld, expressed in Balb/c and other H-2d mice, in complex with the ubiquitously expressed peptide p2Ca; and the MH TCR, which recognizes the MHC class I molecule H-2Db, expressed in B6 and other H-2b mice, in complex with the male peptide WMHHNMDLI. In vitro, Foxp3 2C-TCR-transduced B6 CD4+ T cells are hyporesponsive to stimulation and are able to suppress the alloreactive proliferative response of B6 CD4+ and CD8+ T cells to Balb/c splenocytes, consistent with the acquisition of regulatory function. When adoptively transferred to lethally irradiated Balb/c recipients of MHC-mismatched B6 bone marrow and conventional T cells, Foxp3 2C-TCR-transduced B6 CD4+ T cells reduce early proliferation of donor T cells, weight loss and GvHD score in the recipients. Similarly, CD4+ T cells transduced with Foxp3 and the MH-TCR are able to suppress allogeneic responses both in vitro and in vivo. However, while both the 2C-TCR and the MH TCR confer specificity to their cognate antigens in vitro, antigen specificity of suppression is not evident in these in vivo models. In this thesis I show that the endogenous TCR of transduced CD4+ T cells contributes to this lack of specificity, a finding that has important implications for the use of class I-restricted TCRs alongside Foxp3 in CD4+ T cells to direct regulatory activity.
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Pihlgren, Maria. "Phenotypic and functional characterisation of CD8 memory T cells generated in T cell receptor transgenic mice." Lyon, École normale supérieure (sciences), 1998. http://www.theses.fr/1998ENSL0086.
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La memoire immunitaire, c'est-a-dire la capacite du systeme immunitaire a repondre plus rapidement et plus efficacement vis-a-vis d'antigenes deja rencontres dans le passe, permet une immunite protectrice. Cependant, si la reponse immunitaire vis-a-vis d'antigenes secondaires est bien caracterisee, les bases cellulaires et moleculaires de la memoire immunitaire sont encore mal definies. Nous avons utilise des souris transgeniques pour le recepteur d'antigene de lymphocytes t afin de caracteriser la differenciation et le phenotype de lymphocytes t cd8 a memoire. Nos resultats montrent que la majorite des lymphocytes t cd8 primes obtenus dans ce systeme ne se divisent pas et expriment des taux plus eleves de cd44 et ly6c que les lymphocytes t cd8 naifs. Contrairement a d'autres systemes, nous n'avons pas observe de diminution de l'expression de cd45ra et cd45rb a la surface de lymphocytes t cd8 primes. Fonctionnellement, les lymphocytes t cd8 primes sont capables de repondre a une deuxieme stimulation par l'antigene in vivo. In vitro, les lymphocytes t cd8 primes sont actives par des concentrations de peptide 10 a 30 fois plus faibles que les lymphocytes t cd8 naifs en presence d'interleukine-2. De plus, les lymphocytes t cd8 primes produisent cinq fois plus d'interferon-gamma que les lymphocytes t cd8 naifs. Ces lymphocytes t cd8 primes pourraient jouer un role important dans la reponse memoire.
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Kieback, Elisa. "A new safeguard eliminates T cell receptor gene-modified auto-reactive T cells after adoptive therapy." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15819.
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Der adoptive Transfer von TZR-modifizierten T Zellen ist mit potentiellen Risiken verbunden. Autoimmunreaktionen können auftreten, wenn Tumor-assoziierte Antigene auf normalem Gewebe erkannt werden, Fehlpaarung der TZR-Ketten zur Bildung eines autoreaktiven Rezeptors führen oder ein sonst anerger auto-reaktiver endogener Rezeptor aktiviert wird. Auch besteht das Risiko der malignen Transformation der Zelle durch Insertionsmutagenese. Daher ist es notwendig, die transferierten T Zellen im Fall schwerer Nebenwirkungen eliminieren zu können. Derzeit verfügbare Sicherheitsmechanismen sind für die Therapie mit TZR-modifizierten T Zellen ungeeignet. In dieser Arbeit wurde ein neuer Sicherheitsansatz entwickelt, der auf einem TZR-intrinsischen Depletionsmechanismus beruht und TZR-veränderte T Zellen eliminieren kann. Durch Einfügen eines myc-tags in murine (OT-I, P14) und humane (gp100) TZRs konnten TZR-exprimierende T Zellen in vitro und in vivo mittels eines myc-spezifischen Antikörpers depletiert werden. Die T Zellen behielten vergleichbare Funktionalität hinsichtlich Antigenerkennung und Zytokinsekretion wie Zellen, die den Wild-Typ Rezeptor exprimierten. Die Depletion adoptiv transferierter T Zellen verhinderte lethalen Diabetes in einem Mausversuch. Im verwendeten Modell wurden Splenozyten, die einen myc-getagten OT-I TZR exprimierten, in RIP-mOVA Mäuse injiziert, welche in den Inselzellen des Pankreas das OT-I-spezifische Antigen Ovalbumin exprimieren. Zerstörung der Inselzellen durch die T-Zellen induzierte lethalen Diabetes in unbehandelten Mäusen. Tiere, denen ein myc-spezifischer Antikörper verabreicht wurde, zeigten keine Symptome. Dieser neuartige Sicherheitsmechanismus erlaubt es, adoptive T Zelltherapie abzubrechen, falls schwere Nebenwirkungen auftreten. Im Gegensatz zu früheren Strategien muss kein zusätzliches Sicherheitsgen eingebaut werden und die Sicherheit des Ansatzes wird durch Verlust oder Herunterregulierung des Transgens nicht beeinflusst.Adoptive transfer of TCR gene-modified T lymphocytes into patients is associated with potential risk factors. First, auto-immunity may occur if a tumor-associated antigen is targeted on normal tissue, if TCR chain mispairing leads to the formation of an auto-reactive receptor or if an otherwise anergic endogenous receptor specific for an auto-antigen becomes activated. Second, retroviral integration could lead to malignant transformation of the T cell. Therefore, it is essential to have the possibility to deplete the transferred T cells in vivo in case of severe side effects. The available safety modalities comprise disadvantages rendering them less feasible for the application in therapy with TCR gene-modified T cells. In this study, a safeguard based on a TCR-intrinsic depletion mechanism has been developed that eliminates auto-reactive TCR-redirected T cells. By introducing a myc-tag into the murine (OT-I, P14) or human (gp100) TCRs it was possible to deplete TCR-expressing T cells in vitro and in vivo with a myc-specific antibody. The T cells maintained equal function compared to cells expressing the wild-type receptor as shown by antigen binding and cytokine secretion. Importantly, the in vivo depletion of adoptively transferred T cells prevented disease in an auto-immune mouse model. Here, splenocytes transduced with a myc-tagged OT-I TCR were injected into RIP-mOVA mice expressing the OT-I-specific antigen ovalbumin in the pancreatic beta-cells. Destruction of these cells by the adoptively transferred T cells led to severe diabetes in untreated mice. Animals receiving a myc-specific antibody after T cell transfer showed no increase in blood glucose levels. The developed safeguard allows termination of adoptive therapy in case of severe side-effects. The strategy is superior to previous ones as it relies on a TCR-intrinsic mechanism which does not require introduction of an additional gene and safety is not hampered by loss or low expression of the transgene.
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Zhang, Hao. "T cell antigen receptor binding and initial signal transduction." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669994.
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Boucher, Louis-martin. "T-cell receptor associated signals that modulate lymphocyte homeostasis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0028/NQ49933.pdf.
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Duszczyszyn, Danielle Andrea. "T-cell receptor excision circle content in multiple sclerosis." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82228.
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The pathogenesis of Multiple Sclerosis (MS), a demyelinating disease of the central nervous system (CNS) with associated early axonal damage, is poorly understood. Considerable data indicate that MS is an inflammatory-mediated autoimmune disease. Normally, the naive T-cell niche is maintained by homeostatic mechanisms and in MS, naive T-cells play a central role in the autoimmune response against CNS antigens. Naive T-cells are produced by the thymus and naive T-cell production by the thymus can be ascertained by quantifying signal joint T-cell receptor excision circles (sjTRECs); episomal products formed during V(D)J T-cell receptor rearrangement. Naive T-cells expressing CD31, a cell surface marker, are reported to be highly enriched with sjTRECs. It was hypothesized that in relapsing remitting MS (RRMS), some process significantly alters T-cell generation in the thymus, as measured by sjTREC content in naive CD4 and naive CD8 T-cells.
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Demaine, A. G. "Immunoglobulin and T cell receptor polymorphisms in immune disease." Thesis, Imperial College London, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376674.
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Habib-Nassif, Anne-Marie. "T cell receptor gene characterisation in experimental autoimmune glomerulonephritis." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412499.
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Choudhuri, Kaushik. "The mechanism of T cell receptor-mediated signal transduction." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433379.
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Chua, I. C. "CD8 co-receptor modifications to enhance T cell immunotherapy." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1419099/.
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TCR gene transfer can generate tumour antigen-specific T cells for adoptive immunotherapy. Following TCR gene transfer, transduced T cells usually display the same functional avidity as the parental clone from which the TCR was isolated. However, tumour-antigen specific T cells typically recognize over-expressed self-antigen and are often of low/moderate avidity. It is known that optimal recognition of target cells by CTL requires binding of the cognate peptide MHC class I complex (MHCI) by both TCR and the CD8 co-receptor. Some CD8β chain mutations have been shown to increase CD8 binding affinity with peptide/MHCI and enhance T cell effector function. Murine CD8β chain mutants were generated affecting MHC binding sites (L58R, S53L, S54V and L58R/I25A) or glycosylation sites (T120A, T121A, T124A, and T120A/T121A/T124A). The mutated CD8β molecules were introduced into murine splenocytes using retroviral vectors together with tumour antigen-specific TCRs. The CD8β mutants or control CD8β wild type (WT) chains were first introduced into CD8aa T cells obtained from CD8β knockout mice. All T cells were co-transduced to express the murine F5-TCR which recognizes the model tumour antigen, influenza A nucleoprotein (NP366) presented by H2-Db. The L58R MHC binding CD8 co-receptor mutant (L58R) demonstrated better IFN-γ and IL-2 production in response to relevant peptide while the CD8 glycosylation mutant (T120A/T121A/T124A) mutant demonstrated the opposite effect. The in vitro function of CD4+ T cells transduced with F5-TCR showed that IL-2 and IFN-γ production was enhanced with CD8 co-receptor. In addition, introducing a L58R mutation in the CD8 co-receptor could further increase this effect. The effects of the human CD8 co-receptor with a homologous mutation (I59R) was also investigated in human CD4+ T-cells with a CMV-specific TCR. In vivo studies showed that introducing the F5-TCR alone did not endow CD4+ T cells with significant protection against injected lymphoma cells expressing NP366. However adding CD8 co-receptor to the CD4+ T cells enhanced tumour protection. The genetically modified CD4+ T cells persisted for greater than three months in surviving mice and when re-challenged with antigen the CD4+ T cells with both F5- TCR and CD8 co-receptor had greater proliferative capacity and had more central memory phenotype cells.
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Moysi, Eirini. "T-cell receptor (TCR) usage in HIV-2 infection." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:ea3a066f-0043-4c71-88ec-2369de642460.
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Long-term non-progressors (LTPNs) in HIV infection target the structural protein Gag more frequently than individuals who progress to disease. However, the targeting of Gag per se does not always distinguish these two groups. Various factors have been put forth as likely explanations for this discrepancy including differences in the breadth and magnitude of observed responses, the HLA type of the host, the nature of the individual epitopes targeted and the ability of the virus to mutate these antigenic regions. The purpose of this thesis was to examine, using PBMCs isolated from HIV-2 infected LTNPs and CTL clones established in vitro, the clonotypic architecture and quality of an immunodominant HIV-2 Gag-specific response directed towards the HLA-B*3501-restricted epitope NPVPVGNIY (NY9: Gag245-253). The data presented in this thesis show that in spite of the expression of multiple inhibitory receptors on the surface of NY9-specific CD8+ T-cells, the NY9-response, which is a clonotypically 'private' response, bears a signature characterised by an increased cytotoxic sensitivity and the production of an array of cytokines, most notably IFN-γ and MIP-1β. Moreover, the results of this thesis indicate that the NY9-specific CD8+ T-cells are able to cross-recognise and lyse target B-cells pulsed with the corresponding HIV epitope PY9 and its variants at functional avidities (EC50) that are close to those exhibited by PY9-specific T-cells. However, not all mobilised TCR clonotypes are equally sensitive or equally cross-reactive. When individual CTL clones were studied it emerged that dominant clonotypes within the NY9-specific CD8+ T-cell memory pool possessed a higher avidity for tetramer and sensitivity for antigen than subdominant ones and demonstrated a better cross-reactive potential towards variants of the HIV-2 epitope. Hence, future HIV vaccine strategies may benefit from the inclusion of epitopes like NY9, the presentation of which appears to mobilise CD8+ T-cells with superior functional profiles.
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Bunztman, Adam, Benjamin Vincent, Harsha Krovi, Shaun Steele, and Jeffrey Frelinger. "The LCMV gp33-specific memory T cell repertoire narrows with age." BioMed Central, 2012. http://hdl.handle.net/10150/610159.
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BACKGROUND:The memory response to LCMV in mice persists for months to years with only a small decrease in the number of epitope specific CD8 T cells. This long persistence is associated with resistance to lethal LCMV disease. In contrast to studies focused on the number and surface phenotype of the memory cells, relatively little attention has been paid to the diversity of TCR usage in these cells. CD8+ T cell responses with only a few clones of identical specificity are believed to be relatively ineffective, presumably due to the relative ease of virus escape. Thus, a broad polyclonal response is associated with an effective anti-viral CD8+ T cell response.RESULTS:In this paper we show that the primary CD8+ T cell response to the LCMV gp33-41 epitope is extremely diverse. Over time while the response remains robust in terms of the number of gp33-tetramer+ T cells, the diversity of the response becomes less so. Strikingly, by 26months after infection the response is dominated by a small number TCRbeta sequences. In addition, it is of note the gp33 specific CD8+ T cells sorted by high and low tetramer binding populations 15 and 22months after infection. High and low tetramer binding cells had equivalent diversity and were dominated by a small number of clones regardless of the time tested. A similar restricted distribution was seen in NP396 specific CD8+ T cells 26months after infection. The identical TCRVbeta sequences were found in both the tetramerhi and tetramerlo binding populations. Finally, we saw no evidence of public clones in the gp33-specific response. No CDR3 sequences were found in more than one mouse.CONCLUSIONS:These data show that following LCMV infection the CD8+ gp33-specific CD8 T cell response becomes highly restricted with enormous narrowing of the diversity. This narrowing of the repertoire could contribute to the progressively ineffective immune response seen in aging.
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Laugel, Bruno. "Study of the interplay between antigen T-cell receptor and co-receptor in balancing the specificity and degeneracy of cytotoxic T-cell response." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437180.
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Brändle, Daniel. "Ontogeny of thymocytes and anti-viral cytotoxic T-cell responses studied in T-cell receptor transgenic mice /." [S.l.] : [s.n.], 1993. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10334.
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Shenderov, Eugene. "In vivo and In vitro Studies of T-Cell Receptor-ligland-MHC Affinity and T-Cell Function." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504593.
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Holland, Stephen. "The role of germline-encoded T cell receptor complementarity determining regions in T cell selection and function." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/10725.
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αβ T cell Receptors (TCR) recognise peptide antigen (p) presented on Major Histocompatability Complexes (MHC) via Complementarity Determining Regions (CDRs). TCRs are required to respond to a vast plethora of differing antigens and the CDR regions are suitably diverse, encoded by an array of gene-segments, which recombine during T cell development to generate diverse repertoires of TCRs. CDR1 and 2, which predominantly interact with the MHC, are encoded within gene-segments, and are subject to evolutionary pressure. However, CDR3 loops are non-germline and created through junctional diversity. TCRs are ‘MHC restricted’ and only respond to antigen in the context of MHC. An influential theory proposes that CDR1 and 2 have co-evolved with MHC and as such are inherently predisposed towards MHC recognition. This thesis used preliminary data derived from whole genome analysis of TCR CDR1 and 2 diversity relative to those of related immunoglobulins (which are not MHC restricted) to determine if there is any relationship between germline CDR diversity and MHC restriction. Conventional mutagenesis involving substituting CDR1 and 2 with artificial peptide linkers and replacement of βCDR1 and 2 with those of the related yet MHC unrestricted γTCR chain was carried out in concert with a novel system that embedded recombination cassettes into the CDR1 or 2 allowing in vivo generation and selection of a library of non-germline CDR1 or 2 mutants. Collectively, these data strongly infer a lack of requirement of germline CDR sequences in mediating MHC recognition in both pMHC-mediated T cell development and function. However, alteration of the germline sequence did affect the efficiency of T cell development, preference of MHC class type and the diversity of the subsequent T cell repertoire. Thus, germline CDR structures may facilitate a more diverse array of MHC docking modes to maximise the resultant TCR repertoire, contributing to an increased capacity for cross-reactivity, rather than imposing MHC restriction.
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Chain, Jennifer Lee. "Elucidating the mechanisms of the human [alphabeta] vs. [gammadelta] lineage decision and the details of [gammadelta] thymocyte development." Oklahoma City : [s.n.], 2005.
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Pollard, Tracey Elizabeth. "A study of T-cell receptor usage in allergic asthma and analysis of a humanised T-cell receptor transgenic model of immunity to allergen." Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/11868.
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Robinot, Rémy. "Lymphomes Natural-Killer T cells (NKT) : impact des stimulations antigéniques chroniques et mécanismes de la lymphomagénèse." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1255/document.
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Les lymphomes T périphériques (PTCL) sont des néoplasmes rares et agressifs représentant environ 12% des lymphomes chez l’Homme. Nos travaux récents dans des souris p53-/- ont révélé une nouvelle entité de PTCL, émergeant de cellules Natural-Killer T-cell (NKT), un type particulier de lymphocyte T reconnaissant des antigènes lipidiques. Nous avons montré que ces lymphomes NKT (PTCL-NKT) présentent des caractéristiques de NKT stimulés chroniquement, et que la lymphomagenèse est initiée via l’activation chronique du TCR. Chez l’Homme, de nombreux PTCL sont suspectés pour être associés à des stimulations antigéniques chroniques, mais les mécanismes de transformation impliqués sont encore mal connus. Borrelia burgdorferi (Bb), l’agent responsable de la maladie de Lyme, provoque des infections chroniques dont l’implication dans certains lymphomes T cutanés (CTCL) a été suggérée. Cependant, cette observation manque de preuves cliniques et expérimentales. De manière intéressante, Bb est connue pour exprimer des glycolipides activateurs des NKT. Nous avons donc infecté des souris p53-/- avec des Bb vivantes, et montré que l’infection augmente significativement la fréquence des PTCL-NKT. Par traitement antibiotique précoce de souris infectées et par injections de Bb inactivées, nous avons également démontré que la chronicité de l’infection est nécessaire au développement de ces lymphomes. L’analyse phénotypique de ces PTCL-NKT a confirmé nos observations précédentes, montrant des caractéristiques de cellules NKT activées chroniquement, telles que l’expression de marqueurs d’activation et d’exhaustion (perte de NK1.1, surexpression de PD-1). Ces résultats suggèrent une implication de Borrelia dans la lymphomagenèse T. En se basant sur l’analyse de différents marqueurs phénotypiques et de leur production cytokinique, nous avons également montré que ces lymphomes présentent un profil dérégulé se rapprochant du sous-type NKT2. Une étude génomique par séquençage whole-exome sur 6 PTCL-NKT a révélé de larges pertes récurrentes du chromosome 13. Au sein de la zone minimale de délétion, nous avons identifié Jarid2, codant un facteur épigénétique impliqué dans le développement NKT par une activité histone-methytransférase. Ce gène est retrouvé altéré dans 20% des CTCL. De manière intéressante, les souris Jarid2-/- présentent une expansion périphérique de NKT au profil immature/NKT2, partageant donc des caractéristiques avec les PTCL-NKT. La perte de Jarid2 a été détectée dans presque tous les PTCL-NKT. Nous avons confirmé la perte de Jarid2 au niveau ARN et protéique. Nos résultats préliminaires montrent une hypométhylation de la lysine 9 de l’histone H3 (H3K9), la cible de Jarid2, soutenant un effet fonctionnel dans la physiopathologie des PTCL-NKT. Par conséquent, nous pensons que la perte de Jarid2 pourrait être un événement important de la lymphomagenèse NKT, puisque de plus en plus d’altérations de facteurs épigénétiques sont retrouvées dans les PTCL humains. Pour réponse à cette question, nous sommes notamment en train de générer des souris p53-/- x Jarid2-/-. En conclusion, nos données viennent renforcer le concept selon lequel certaines infections peuvent initier la transformation des cellules T par l’activation chronique du TCR. Nous avons également identifié un nouveau facteur épigénétique potentiellement impliqué dans la lymphomagenèse NKTPeripheral T-cell lymphomas (PTCL) are aggressive and heterogeneous neoplasms that represent around 12% of Human lymphomas. Our recent work in p53-/- mice revealed a new PTCL entity, arising from Natural-Killer T-cell (NKT), a particular type of T cell recognizing lipidic antigens. We found that NKT lymphomas (NKTL) present features of chronically stimulated NKT-cells and that lymphomagenesis is driven through chronic TCR activation by microbial glycolipids. In human, many PTCL are suspected to be associated with chronic antigenic stimulation, but this transformation mechanism is still poorly understood.Borrelia burgdorferi (Bb), the causative agent of Lyme disease, induces chronic infection and has recently been suggested to be involved in cutaneous T-cell lymphomas (CTCL). However, this observation lacks clinical and experimental proofs. Interestingly, Bb is known to express NKT-activating glycolipids. We therefore infected p53-/- mice by live intradermal Bb injection and showed that Bb infection significantly increased NKTL rate. Phenotypic characterization of these NKTL confirmed our previously described features of chronically stimulated NKT-cells, with expression of activation and exhaustion markers (loss of NK1.1, upregulation of PD-1). Based on surface markers, transcription factors and cytokine production analysis, we also found that our lymphomas mostly present a NKT2 subtype profile, sometimes surprisingly mixed with NKT17 or NKT1. Genomic study by whole-exome sequencing on few of these lymphomas revealed recurrent large losses in the chromosome 13. Within the minimal deletion region, we identified Jarid2, a gene involved in NKT development by epigenetic regulation and which is found altered in 20% of CTCL. Jarid2 loss was detected in almost all NKTL. Interestingly, Jarid2-/- mice show increased NKT number in the periphery with an immature/NKT2 phenotype, sharing features with our NKTL.Thus, we believe that Jarid2 loss may be an important event in NKT lymphomagenesis, as more and more epigenetic factors are found mutated in several human PTCL. To answer this question we are currently breeding p53-/- x Jarid2-/- mice. In conclusion, our data reinforced the concept that chronic bacterial activation of T-cells through their TCR can effectively drive T-cell transformation. We also identified a new potential epigenetic factor that may be involved in lymphomagenesis
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Ueda, Maki. "Expression of functional interleukin-21 receptor on adult T-cell leukaemia (ATL) cells." Kyoto University, 2005. http://hdl.handle.net/2433/144754.
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Fairbairn, Camilla Jayne. "Searching for the missing T Cell Receptor (TCR) in Anaplastic Large Cell Lymphoma (ALCL) : surplus to requirements or a protagonist in lymphomagenesis?" Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273245.
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Anaplastic Large Cell Lymphoma (ALCL) is a peripheral T cell lymphoma divided into three distinct entities: ALCL, Anaplastic Lymphoma Kinase (ALK)+, ALCL ALK- and cutaneous ALCL. In the majority of ALCL, ALK+, ALK is expressed as the result of a chromosomal translocation generating Nucleophosmin 1(NPM)-ALK, which is considered the main driver. ALCL have an unusual immunophenotype; they rarely express a T cell receptor (TCR), but are often positive for CD4 and produce cytotoxic proteins such as perforin and Granzyme B, but in the absence of CD8, questioning the origin and pathogenesis of this malignancy. Expression of NPM-ALK in mice from the T-cell specific CD4 promoter gives rise to thymic lymphomas not modelling human ALCL suggesting that other events and/or expression of NPM-ALK at a defined stage of T cell ontogeny is required for peripheral T cell lymphoma development. Indeed, back-crossing the CD4/NPM-ALK line onto a RAG competent, MHC class I restricted ovalbumin-specific TCR, OTI transgenic line (CD4/NPM-ALK/OTI) permits peripheral lymphoma development mimicking human ALCL (but CD4/NPM-ALK/OTII mice still develop thymic lymphoma); tumours contain cells histopathologically identical to ALCL hallmark cells. Interestingly, peripheral tumours developing in this model also lack cell surface expression of the OTI TCR in fitting with observations of a lack of TCR expression on human ALCL. It follows that stimulation of T cells in vivo by infection with MHV-ova prevents lymphomagenesis suggesting that the TCR is detrimental to tumour growth. Indeed, strong stimulation via the TCR of NPM-ALK-expressing primary T cells in vitro, impedes cell proliferation but cell growth is favoured when a weaker stimulus is employed. Overall, data presented in this thesis identifies a potential mechanism of lymphomagenesis accounting for the unusual immunophenotype of ALCL and an explanation as to why cells lack a TCR and associated proximal signaling.
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Böhm, Stefanie [Verfasser], and Lars [Akademischer Betreuer] Nitschke. "Adoptive T-cell-receptor transfer to examine human T-cell immunology in vitro / Stefanie Böhm. Betreuer: Lars Nitschke." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1033688193/34.
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Bas, Anna. "Extrathymic T cell receptor gene rearrangement in human alimentary tract." Doctoral thesis, Umeå University, Clinical Microbiology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-169.
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T lymphocytes regulate the initiation, duration, and magnitude of adaptive immune responses and function as effector cells in cell mediated immunity. To become immunologically competent they must generate functional antigen receptors. This process takes place in the thymus and requires somatic recombination of T cell receptor (TCR) genes. It is mediated by the endonucleases recombination activating gene-1 (RAG1) and RAG2. Although the thymus regresses at puberty, T cells are present throughout life implying that other tissues must provide the proper milieu for T cell development. This thesis describes extrathymic T cell maturation in man. RAG1, RAG2, and the preTα-chain (pTα), which is exclusively utilized in developing T cells, were used as markers for TCR gene rearrangement. Two new exons (1A and 1B) encoding sequences in the 5’ untranslated region (5’UTR) of mRNA were discovered in the human RAG1 gene. The previously described 5’UTR exon (renamed 1C) was located between the new exons and exon 2, the latter containing the entire coding sequence. We found that small intestinal lymphocytes of the T cell lineage expressed the new exons in three different splice forms. RAG1 mRNA containing the 1C exon was not expressed in small intestinal lymphocytes. In contrast, splice forms containing the 1A exon were not expressed in thymocytes. RAG1 and pTα mRNA expressing lymphocytes were seen both within the epithelium and in lamina propria. Thymocyte-like CD2+CD7+CD3-, CD4+CD8+, CD1a+, and IL7-R+ lymphocytes were identified in the small intestinal mucosa. CD2+CD7+CD3- cells had the highest expression levels of mRNA for RAG1 and pTα, suggesting that the small intestinal mucosa is indeed a site for T cell maturation. Small intestinal T lymphocytes were also shown to kill via the Fas/FasL pathway in a TCR/CD3 independent manner and via the perforin/granzyme pathway in a TCR/CD3 dependent manner. The Fas/FasL-mediated cytotoxicity may reflect an ongoing selection process of extrathymically maturated T cells.
The nasopharyngeal tonsil is the major inductive site for immune reactions against inhaled antigens. Previous demonstration of RAG1 expression in tonsillar B cells was interpreted as antigen driven receptor revision. The present study confirms the expression of RAG1 in B cells. We also found that RAG1, RAG2, and pTa mRNAs were expressed in lymphocytes of the T cell lineage. A small population of cells with the immature phenotype CD2+CD7+CD3- was demonstrated. This population had the highest expression levels of mRNA for RAG1, RAG2, pTα and terminal deoxynucleotidyl transferase. All four splice-forms of RAG1 mRNA were expressed. RAG1 and pTα mRNA expressing cells were mainly located in the proximity of the surface epithelium and in the outer rim of the follicles. These results suggest that the nasopharyngeal tonsil is a site where extrathymic T cell development and antigen driven TCR revision are occurring in parallel.
Celiac disease (CD) is a small intestinal enteropathy characterized by permanent intolerance to gluten. Gluten reactive intestinal T cells are central in the pathogenesis and CD can be regarded as a failure to maintain tolerance to this food antigen. Expression of the RAG1 1A/2 splice form was significantly decreased in small intestinal T cell subsets of CD patients suggesting that impaired TCR gene rearrangement could contribute to failure of maintain tolerance in CD.
Together, these findings show that both small intestinal and nasopharyngeal tonsillar lymphocytes of T cell lineage have the molecular machinery for antigen receptor rearrangement and that thymocyte-like lymphocytes are present in both tissues. Thus these organs are likely sites of T lymphocyte ontogeny as well as for secondary T cell receptor rearrangement in man.
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Cannons, Jennifer. "Signal transduction by the T cell costimulatory receptor, 4-1BB." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63680.pdf.
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