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1
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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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.
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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
5
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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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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Tyznik, Aaron Jacob. "CD4+ T cell help for CD8+ T cell responses /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8314.
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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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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.
10
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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Thümmler, Katja. "Immune regulation through homotypic T cell, T cell interaction = Immunregulation durch homotypische T-Zell-T-Zell-Wechselwirkungen." kostenfrei, 2010. http://d-nb.info/100248281X/34.
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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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Ferreira, Cristina da Conceição Varandas. "Naive T cell survival : analysis of transgenic monoclonal T cell populations." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250701.
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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.
15
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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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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Murray, Anna. "T cell clonality in coeliac disease and enteropathy associated T cell lymphoma." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241223.
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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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Bangs, Sarah Christine. "Bystander T cell activation." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491311.
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T cell responses are subject to several layers of regulation in order to prevent a detrimental effect on the host. Bystander T cell activation occurs via TCR-independent mechanisms, and as such evades certain control checkpoints. The apparent irrationality of this concept, coupled with the finding that the overwhelming majority ofT cells activated during viral infection are antigen-specific, has lead to a debate over the existence of the phenomenon. In this study, I sought to build upon previous work with murine models, to demonstrate the existence of bystander T cell activation in primary human T cells following initial stimulation of a distinct population of antigen-specific T cells with staphylococcal enterotoxin B (SEB). Furthermore, it has been established that this occurs in the absence of any opportunity for TCR cross-reactivity. Further investigation was made into the mechanism of activation, and the phenotype and function of bystander activated T cells. Phenotypic analysis indicated that bystander T cell activation in the SEB system occurred preferentially within a particular T cell subset. Distinct characteristics were identified amongst directly activated T cells and bystander activated T cells. The functional outcome with regards to proliferative capacity, apoptosis induction, and suppression by regulatory T cells was also investigated, Microarray analysis of resting, bystander, and directly activated T cells revealed distinct gene expression profiles, and analysis of differentially expressed genes supported an absence of TCR stimulation within the bystander population. Data furthermore indicated distinct mechanisms of apoptosis for bystander and directly activated T cells. Candidate cytokines implicated by the data were followed up with neutralisation assays. Taken together, the data support the hypothesis that bystander T cell activation induces a partial activation state in a proportion of memory T cells, which is followed by apoptosis, which may provide immunological space for newly generated antigen-specific memory T cells, while eroding pre-existing memory populations.
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Chan, Chi Wei Cliburn. "Modelling T cell activation." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396213.
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Alsubki, R. A. "Editing T cell specificity." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1561576/.
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Allogeneic hematopoietic stem cell transplantation is considered to be the main means of treatment for hematological malignancies. However, disease relapse and graft versus host disease remain the major cause of death post transplantation. To reduce the risk of graft versus host disease and in order to improve the graft versus leukemia effect, genetically engineered T-cells are used to express tumor specific antigens. This is either through the transfer of a recombinant antigen-specific T cell receptor (TCR) or through the introduction of antibody-like recognition in chimeric antigen receptors (CARs) toward tumor-associated antigens. These methods have made substantial advances. Nevertheless, the complexity in modifying and producing autologous specific T-cell products for each patient is a major barrier to the broader application of this approach. In this context, the ability to generate an “off-the-shelf” mismatched donor-derived therapeutic T cell product was investigated. To overcome HLA barriers and to eliminate the risk of graft versus host disease, tailored transcription activator-like effector nucleases (TALENs) knocking out the expression of endogenous T cell receptor was utilised. Also, the potential of engineered meganucleases and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) to disrupt the genomic sequence of the T cell receptor was evaluated. Large numbers of recent clinical trials have suggested that in vivo persistence and expansion having a potent anti-tumor activity of the genetically engineered T cells is crucial to have a robust clinical response. In order to generate a T cell product possessing these previous features, we have investigated the ability to engineer naïve cord blood T cells toward specific tumor antigens. Due to their naivety, the higher telomeres activity, low graft-versus-hostdisease, amongst several other features, have the potential of making cord blood an optimal source for the production of a universal allogeneic engineered T cell therapy. Moreover, preclinical models have demonstrated that culturing naïve T cells in the presence of interleukin-7 and interleukin-15 might retain the modified cells in their naïve like phenotype. In conclusion, delivery of CD19CAR genes using lentiviral vectors into naïve cord blood T cells could form the basis of generating a universal cell bank of therapeutic T cells against B cell lymphoma. With further optimisation to improve efficiency, this could be combined with TALENs for site-specific disruption of the endogenous T cell receptor to eradicate the risk of graft-versus-host disease.
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Lara, Oscar R. "Immunomagnetic cell separation further applications of the quadrupole magnetic cell sorter /." Columbus, Ohio : Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5fnum=osu1064338539.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xxi, 179 p.; also contains graphics (some col.). Includes abstract and vita. Advisor: Jeffrey, Dept. of Chemical Engineering. Includes bibliographical references (p. 160-169).
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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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Sun, Joseph C. "The role of CD4 T cell help during the CD8 T cell response /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8334.
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Paiva, Ricardo de Sousa. "T cell Maturation and Regulatory T Cell Differentiation:From the Thymus to the Periphery." Doctoral thesis, Universidade Nova de Lisboa.Instituto de Tecnologia Química e Biológica, 2012. http://hdl.handle.net/10362/10587.
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Immunological tolerance, that is, the failure to mount an immune response to
an otherwise immunogenic molecule, is one of the fundamental questions in
immunology. The fact that lymphocytes express antigen receptors that are
generated randomly and have the potential to recognize any conceivable
antigen, adds another puzzle to the physiology of immunological tolerance.
The other side of the coin, the general absence of immune responses to self
antigens, is ensured by a tight regulation and several selection steps during
T and B cell differentiation. One of these processes is the differentiation of
regulatory T cells (Treg). While developing in the thymus, T cell clones
bearing receptors with high affinity/avidity to antigens present at the time of
differentiation may be eliminated by apoptosis or, alternatively, express
Foxp3 and become Treg. Treg are key players in the regulation of
immunological tolerance since humans and mice with complete loss of
function variants of this gene develop fatal autoimmune conditions early in
life.(...)Dissertation presented to obtain the Ph.D degree in Immunology
30
Mofolo, Boitumelo. "Regulated T cell pre-mRNA splicing as genetic marker of T cell suppression." Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/3071.
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Gozalo, Sara. "The Role of γс Cytokines in T Cell Development, T Cell Homeostasis and CD8+ T Cell Function: A Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/140.
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T lymphocytes are essential components of the immune system and as such are continually regulated by a variety of factors. Every step of their development, survival and function is tightly monitored to ensure their ability to recognize most foreign agents and mount adaptive immune responses during pathogenic infections, while remaining tolerant to self-antigens. Among the many factors that participate in the regulation of T cell development and function are the cytokines. Cytokines that signal through the common gamma (γс) chain and the Janus kinase 3 (Jak3) include IL-2, -4, -7, -9, -15, and -21 and have been implicated in the regulation of every stage in the life of a T cell. Therefore, it is not surprising that mutations in the γс chain or Jak3 lead to a SCID condition in humans and mice. Specifically, Jak3-deficient mice are characterized by a reduction in thymic cellularity and dysregulated T cell homeostasis. They have an expansion of memory-like CD4+ mature T cells and an almost complete absence of mature CD8+ T cells. By investigating the TCR repertoire of CD4+ T cells in the thymus and spleen of Jak3-/- mice, I deduced that the CD4+ T cell activation and expansion is TCR-specific and takes place in the periphery of the mice. After crossing Jak3-deficient mice to Bcl-2 transgenic mice I showed that the developmental block observed in Jak3-/- mice could not be rescued by the anti-apoptotic factor, despite the fact that its expression did increase, slightly, the total numbers of developing thymocytes. The enforced expression of Bcl-2 was also not sufficient to revert the dysregulation of T cell homeostasis in Jak3-/- mice. Finally, in order to further understand the role played by γс cytokines during T cell function, I investigated the ability of mature Jak3-/- CD8+ T cells to become activated and differentiate into effector cells in response to a viral infection. My results indicate that CD8+ T cells are activated and proliferate in response to a viral infection, but their survival, as well as their ability to proliferate and differentiate into effector cells are greatly impaired, resulting in the inability of Jak3-deficient mice to mount a protective response.
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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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Chtanova, Tatyana Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "T cell transcriptomes: uncovering the mechanisms for T cell effector function through gene profiling." Awarded by:University of New South Wales. Biotechnology and Biomolecular Sciences, 2005. http://handle.unsw.edu.au/1959.4/22029.
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T cells are at the heart of the adaptive immune response. They mediate many important immunological processes that provide protection against viruses, bacteria and other pathogens. The aim of the work described in this thesis was to use gene expression profiling to gain insights into different aspects of T cell biology. In particular we wanted to examine the mechanisms and identify the genes that underlie T cell effector function. IFN-g-producing Th1 cells are a major effector subset that protects against intracellular pathogens, while Th2 cells produce IL-4, IL-5 and IL-13 and mediate protection against large extracellular pathogens. Microarray profiling of gene expression in mouse and human Th1 and Th2 cells, as well as mouse Tc1 and Tc2 cells, identified a number of novel markers of these T cells which may have important roles in T cell differentiation/function. We found that T cell type, host species and differentiation conditions significantly influenced gene expression profiles generated during T cell polarization. Providing help to B cells for antibody production is the major function of the third effector subset of CD4+ T cells termed T follicular homing or TFH cells. Relatively little is known about the generation of these cells, and the mechanisms of their effector function. Using oligonucleotide microarrays we identified a TFH-specific gene expression signature, which included many novel genes which will undoubtedly enable better identification and characterization of this novel subset. A comprehensive study profiling all the major leukocyte subsets revealed their distinct gene expression signatures and numerous leukocyte subset specific genes. A detailed examination of most major T cell subsets identified distinguishing features of each subset together with gene expression changes associated with T cell activation and exposure to cell culture conditions. In addition, we described a distinctive transcriptional profile for gd T cells and examined the differences between central and effector memory T cells. We also showed that specific gene expression signatures provide a powerful tool for subset classification. Taken together this work provides important insights into T cell differentiation and effector function, and presents a basis for future work examining numerous novel genes relevant to T cell biology.
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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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English, Kieran. "Deciphering the cellular mechanisms promoting CD4+ T cell-dependent intrahepatic CD8+ T cell immunity." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27735.
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The liver is the body’s largest internal organ and assumes many important physiological and metabolic functions. It is also well-established that the liver possesses unique immunological properties and a delicate balance between tolerance and immunity exists within this large organ. CD4 T cell help to CD8 T cells has emerged as a critical factor involved in promoting robust CD8 T cell responses against viral and tumour antigens. Studies in humans and chimpanzees indicate that CD4 T cells are critical for strong intrahepatic CD8 T cell responses and the spontaneous control of hepatitis C virus and hepatitis B virus infections. However, due to limitations of current small animal models, the precise role of CD4 help in orchestrating intrahepatic CD8 T cell responses, and the mechanisms by which CD4 help is transferred to intrahepatic CD8 T cells remains poorly understood. Using an rAAV based approach to express model antigens containing both CD4 and CD8 T cell epitopes specifically in hepatocytes, we first demonstrate that CD4 help enhances the primary expansion of CD8 T cells responding to hepatocyte expressed antigens, which is critical for the generation of a large pool of memory CD8 T cells in the liver, blood and lymphoid tissues. Importantly, we decipher a novel mechanism facilitating the transfer of CD4 help to intrahepatic CD8 T cells: cognate CD40-CD40L licensing of hepatic XCR1 cDC1s in situ within portal tracts and central veins. In deciphering this mechanism, we also uncovered a previously unrecognised interconnected myeloid cell network contained within portal tracts in the steady state and following antigen expression in the liver. Together, these discoveries yield important insights into the mechanisms governing the outcome of intrahepatic immune responses, and suggest avenues for future work, with the possibility of translational research to explore novel therapies to manipulate intrahepatic immunity and hence beneficially alter outcomes in human liver diseases.
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Fukunaga, Akiko. "Altered Homeostasis of CD4+ Memory T cells in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Chronic Graft-versus-Host Disease Enhances T cell Differentiation and Exhausts Central Memory T Cell Pool." Kyoto University, 2008. http://hdl.handle.net/2433/124214.
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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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Xue, Yintong. "Glucocorticoid in T cell differentiation /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3950-0/.
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Lovatt, Matthew. "Control of T cell selection." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313597.
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Sheu, Eric G. "Immunology of T cell vaccines." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288552.
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Lomas, Adrian John. "Poliovirus T cell epitope chimaeras." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318621.
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Demetriou, Philippos. "Regulation of T cell activation." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:a20d2d22-bdc8-407e-a9b5-57d18ae6948a.
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Recognition of a cognate peptide-MHC molecule by its T cell receptor (TCR) triggers a critical cascade of protein re-organisation and clustering at the cell interface. This results in the formation of the immunological synapse (IS), concurrent with and influencing T cell activation. The glycoprotein CD2 with its ligand CD48 (mouse) or CD58 (human) has been shown to act as an important adhesion/co-stimulatory molecule influencing the T cell activation. While initial analysis of the knockout mouse revealed redundancy with LFA-1 and CD28, activity of this pathway has been correlated with enhanced pathogen clearance and autoimmunity in humans, renewing interest. Earlier analysis of CD2 dynamics in Jurkat cells revealed formation of large domains that display centralization similar to the TCR and co-stimulatory receptors like CD28. We have found that ligated CD2 displays a more complex behaviour in previously uncharacterized later stages of IS maturation in primary mouse and human CD4+ T cells. We observed that the CD2-CD58 complexes colocalised with TCR/pMHC microclusters during the formation of the mature IS, characterized by the central supramolecular activation cluster (cSMAC) where TCR signaling is terminated. Upon formation, the CD2-CD58-rich plaques moved outwards to form a 'corolla', a segmented ring outside the LFA-1-ICAM-1 peripheral SMAC (pSMAC). This 'corolla' is enriched in downstream active signalling molecules. We found that the CD2 'corolla' also brings with it other co-stimulatory receptors like ICOS and CD28. We suggest that CD2 rescues TCR and costimulatory signalling complexes that are destined for termination in the cSMAC to a peripheral site where signalling can be sustained, leading to enhanced signal integration. Interestingly, investigation of the classical co-inhibitory receptor PD-1, revealed that PD-1 and CD2 corolla can be segregated under specific conditions but can also colocalise in the periphery of the IS; preliminary data suggests that this is dependent on the expression levels of PD-1. Overall, our results suggest that the expression levels of these co-stimulatory/inhibitory receptors can influence their localisation dynamics within the IS. Most importantly, CD2 expression levels are one of the key factors controlling corolla formation. Our results suggest that the expression levels of the co-stimulatory/inhibitory receptors have functional implications in the IS. Finally, we have investigated the levels of CD2 and PD-1 in the tumour microenvironment where tumour-infiltrating lymphocytes (TILs) are failing to stop tumour growth. Our preliminary data in small cohort of eight colorectal cancer patients were surgical specimens were acquired demonstrate high levels of PD-1 and low expression of CD2 in CD8+ TILs compared to CD8+ T cells found in normal tissue adjacent to the tumour or in peripheral blood CD8+ T cell compartment of healthy individuals. In summary, we are proposing that CD2 acts both as a classic costimulator with strong expression the ability to enhance activation of Src famly kinases and as an organiser or co-stimulatory/inhibitory signalling in the IS.
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Opel, Cary F. (Cary Francis). "T cell mediated combination immunotherapy." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/107075.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, February 2016.Cataloged from PDF version of thesis. "September 2015."
Includes bibliographical references (pages 128-131).
Immunotherapy is a broad treatment strategy that harnesses the immune system to fight off a particular condition or disease. Cancer immunotherapy is the specific application of agents designed to interact or stimulate the immune system to fight off tumors. Treatments as diverse as passive antibody therapy, cytokine support, and comprehensive adoptive T cell transfer make up the broad field of immunotherapeutics. Due to the naturally complex interactions inherent in the immune system, there are many options for therapeutic intervention, however, this same complexity makes it extremely difficult to optimize treatment strategies. Because of this, research into developing new immunotherapies, optimizing existing immunotherapies, and designing new combinations of immunotherapies is still critical in the fight against cancer. Although there have been ongoing successes of individual immunotherapies in the clinic, the complexity and interdependence of the immune system suggests that any single therapeutic intervention will be insufficient to reject established malignancies. Increased interest in applying combinations of immunotherapies in the clinic requires more thorough preclinical work to guide the designs of these studies. The work presented in this thesis focuses on developing combinations of immunotherapies to treat preclinical models of cancer, as well as studying the underlying mechanism of tumor control. T cells are potent mediators of cytotoxicity and when properly used in adoptive cell transfer (ACT) protocols, can be highly effective in the treatment of cancer. ACT consists of three steps: 1) harvesting and purifying T cells from the patient, 2) enriching or modifying the T cells to become tumor specific, and 3) reinfusing the T cells along with supporting therapies. Therapies given alongside ACT are often adjuvants designed to enhance T cell response. However, focusing therapies only on enhancing the activity of the transferred T cells may miss out on synergistic effects when other parts of the immune system are simultaneously engaged. To study the effect of adjuvant therapy on ACT, a preclinical murine model was analyzed. Large, established B16F10 tumors were controlled when pmel-1 T cells were given with a course of supportive MSA-IL2 cytokine therapy, however, no cures were observed. When a course of TA99 antibody therapy was added alongside ACT, a high rate of cures was observed. Flow cytometry of both circulating and tumor infiltrating pmel-1 cells showed massive expansion and activation. Additionally, tumor infiltration of neutrophils, NK cells, and DCs were greatly enhanced by adjuvant therapy. DCs in the tumor draining lymph nodes were largely unchanged by the therapies. Engagement of the humoral immune response was also observed in both treatment cases. Surprisingly, antibody therapy did not substantially alter any of the mechanistic observations made in this study, despite its critical role in achieving cures of tumors. While ACT is a highly effective therapy, its clinical applicability is hindered by the complexity of performing T cell transplants and manipulations. A more optimal solution would involve purely injectable treatments that could elicit the same level of tumor specific T cell response in conjunction with potent recruitment of the adaptive immune system against tumors. To achieve this, working in collaboration with the Irvine Lab, combinations of immunotherapy using up to four different components were tested to identify critical factors in the successful rejection of established tumors in preclinical models. The four components of tumor targeting antibody, cytokine support, checkpoint blockade, and cancer vaccine acted synergistically to reject tumors from B16F10, TC-1, and DD-Her2/neu cell lines. The cancer vaccine elicited large numbers of tumor-specific T cells, and acted as a replacement for ACT. By analyzing subset combinations of this full treatment, the roles of each therapeutic component were identified. CD8 T cells and cross-presenting DCs were critical to curing subcutaneous tumors. Cytokine therapy was indispensable for effective tumor control, promoted immune cell infiltration into the tumor, and led to an increase in DCs. In combination with the other therapies, vaccination against a tumor antigen elicited a strong immunological memory response that was able to reject subsequent tumor rechallenge, as well as promote antigen spreading to new epitopes. Successful combinations were demonstrated to be dependent on the recruitment of both the adaptive and innate branches of the immune system. Finally, the efficacy of this combination of treatments was demonstrated by controlling the growth of induced tumors in a BRaf/Pten model. Combination immunotherapy promises a future where synergistic treatments are specifically tailored to individual cancers leading to highly effective responses. However, determining the optimal combination of therapies, the complexity of dosing strategies, and the availability of targeted treatments are all barriers that must be overcome. The analysis presented here will make a significant contribution to the body of knowledge on immunotherapy as it has shown the importance of combining orthogonal immunotherapies in order to get durable cures to established tumors. These results will hopefully encourage combinations of orthogonally acting therapies based on T cells to achieve stronger clinical responses. By determining the necessary requirements for a strong, synergistic response to tumorous growths, more effective combination immunotherapy protocols may be designed in the future.
by Cary F. Opel.
Ph. D.
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Cornish, Georgina. "Regulation of T cell growth." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1446301/.
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This PhD thesis aims to examine the growth of T cells in response to cytokines of the common gamma chain (yc) family, in particular interleukin (IL)-2 and IL- 15. Cell growth is commonly used to describe cells in exponential division however the growth of a cell is defined by its size and volume, which is directly related to the rate of cell metabolism and protein synthesis. Naive T cells are small and circulate around the body maintaining a minimal rate of metabolic activity and protein synthesis. During an immune response naive T cells undergo rapid proliferation and differentiate into effector cells. These cells produce and secrete large amounts of cytokines and effector molecules allowing them to mediate their immune function. The differentiation of antigen activated T cells to mature effectors takes several days and is regulated by cytokines. These cytokines need to maintain high rates of cell metabolism for a prolonged period. Thus the cytokines that regulate proliferation and differentiation of antigen activated T cells need to sustain cell growth. Data presented in this thesis shows differential roles for gamma chain cytokines, specifically IL-2 and IL-15 in the regulation of protein synthesis and uptake of amino acids, whilst maintaining equal mitogenic capacity. This thesis highlights the possible uncoupling of the rate of cellular division and protein synthesis induced by cytokines and defines a unique role for common gamma chain cytokines in regulation of protein synthesis and ultimately the regulation of cellular function.
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Trüb, Marta. "Follicular T helper cell populations." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/20466.
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Humoral immunity provides protection against subsequent infections. Antigen-specific, high-affinity, class-switched antibodies are produced by B cells through rounds of proliferation, B cell receptor rearrangement and selection in the germinal centres (GC). T cells play an essential and indispensable role in this process and in the recent years the term T follicular helper cells (TFH) was coined to describe this cell subset. The aim of my thesis is to investigate whether there is more than one type of T cells within the TFH population and whether it has important functional consequences. Firstly, I use sheep red blood cell immunisation (SRBC) and Salmonella enterica infection to show phenotypical differences between TFH expressing high and low level of surface molecule PD-1. In order to investigate the relationship between different TFH populations gene profiling was carried out on the microarray platform. Detailed transcriptome analysis revealed the discrete nature of isolated TFH cell subsets and provided an overview of their genetic landscape. Secondly, I have investigated the dependence of TFH subsets on cognate interactions with B cell in SRBC model by generating BM chimeras. I have demonstrated that generation of PD-1HI TFH, but not of PD-1LO TFH, depends on antigen presentation by B cells. Furthermore, I have shown that provision of wild-type but not MHC II knock-out B cells rescues PD-1HI formation in BM chimeras after SRBC immunisation. Finally, I have explored plasticity within TFH subsets and showed that none of the populations is in a terminally differentiated state, as they can convert into one another. Thirdly, experiments with S. enterica model revealed that the absence of PD- 1HI TFH is independent of the splenic architecture disruption present within the first week of the response. Surprisingly, co-immunisation studies showed that PD-1HI population is not only present but even enhanced in the group which received both SRBC and S. enterica when compared to single immunisations. The work presented in the thesis documents that there is a significant and previously unappreciated heterogeneity within TFH subset. This knowledge is important for designing optimal vaccine strategies and treating autoimmune diseases, as in both processes the antibody production plays a crucial role and its manipulation (either enhancing or blocking antibody production, respectively) can significantly improve clinical interventions.
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Tigno-Aranjuez, Justine Daphne Tiglao. "Adjuvant Guided T cell Responses." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244035297.
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