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Sutiwisesak, Rujapak. "Natural Polymorphism of Mycobacterium tuberculosis and CD8 T Cell Immunity." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1076.
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Coevolution between Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, and the human host has been documented for thousands of years. Interestingly, while T cell immunity is crucial for host protection and survival, T cell antigens are the most conserved region of the Mtb genome. Hypothetically, Mtb adapts under immune pressure to exploit T cell responses for its benefit from inflammation and tissue destruction for ultimately transmission.
EsxH, a gene encoding immunodominant TB10.4 protein, however, contains polymorphic regions corresponding to T cell epitopes. Here, I present two complementary analyses to examine how Mtb modulates TB10.4 for immune evasion. First, I use a naturally occurring esxH polymorphic clinical Mtb isolate, 667, to investigate how A10T amino acid exchange in TB10.4 affect T cell immunity. To verify and identify the cause of the immunological differences, I construct isogenic strains expressing EsxHA10T or EsxHWT. In combination with our recent finding that TB10.44-11-specific CD8 T cells do not recognize Mtb-infected macrophages, we hypothesize that TB10.4 is a decoy antigen as it distracts host immunity from inducing other potentially protective responses. I examine whether an elimination of TB10.44-11-specific CD8 T cell response leads to a better host protective immunity. The studies of in vivo infection and in vitro recognition in this dissertation aim to provide a better understanding of the counteraction between immune evasion and protective immunity.
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Rydyznski, Carolyn E. "Natural Killer Cell Regulation of Humoral Immunity." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535377157934852.
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Borysiewicz, L. K. "Cell mediated immunity to human cytomegalovirus infection (cytotoxic T cell and natural killer cell mediated lysis of human cytomegalovirus infected cells)." Thesis, Imperial College London, 1986. http://hdl.handle.net/10044/1/37949.
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Zhou, Jianfang. "The immunological roles of human macrophages in avian influenza virus infection." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36611153.
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Zhou, Jianfang, and 周劍芳. "The immunological roles of human macrophages in avian influenza virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36611153.
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Mukherjee, Sumanta. "LPS induced T[subscript]H2 (Interleukin-4) cytokine production in macrophages and its regulation." Connect to full text in OhioLINK ETD Center, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1207743729.
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Dissertation (Ph.D.)--University of Toledo, 2008."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 161-180.
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Mayes, Kimberly. "The Role of the Nucleosome Remodeling Factor NURF in Inhibiting T and Natural Killer Cell Mediated Antitumor Immunity by Suppressing Tumor Antigenicity and Natural Cytotoxicity Receptor Co-ligands." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4770.
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Tumor immunoediting is a dynamic process in which the immune response attacks tumor cells by detecting danger signals and tumor antigens. In order to survive, tumor cells develop mechanisms to avoid detection or destruction by the immune system. To counteract this, several strategies are being developed to enhance the antitumor immune response, including the depletion of immunosuppressive cells, enhancing the activation of antitumor immune cells and increasing tumor cell immunogenicity. These therapies have seen limited success individually, however, and it is likely that combination therapy with novel targets will be necessary to see reproducible beneficial responses. Epigenetic modifications are attractive therapeutic targets because they are reversible and affect gene expression in cancer cells. Within this framework, this study aimed to elucidate the role of the chromatin remodeling complex nucleosome remodeling factor (NURF) in cancer immunoediting by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. Using two syngeneic mouse models of cancer, BPTF was found to suppress T cell antitumor activity in the tumor microenvironment. In vitro, enhanced cytolytic activity was observed for individual CD8 T cell clones only from mice bearing BPTF-silenced tumors, implicating the involvement of novel antigens. Mechanistic investigations revealed that NURF directly suppresses the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. PSMB8 inhibition reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor cell antigenicity and its depletion improves CD8 T cell antitumor immunity. In a concurrent study using different tumor lines, BPTF was also found to suppress natural killer (NK) cell antitumor immunity in vivo. Enhanced NK cell cytolytic activity toward BPTF-depleted targets in vitro was dependent on the natural cytotoxicity receptors (NCR). Molecular studies revealed that BPTF directly activates heparanase (Hpse) expression, resulting in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans. Thus, NURF represses NCR co-ligand abundance and its depletion enhances NK cell cytotoxicity. Therefore, NURF emerges as a candidate therapeutic target to enhance CD8 T or NK cell antitumor immunity.
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Watkin, Levi B. "The Role of Heterologous Immunity in Mediating Natural Resistance to Infection in Human Subjects: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/586.
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Heterologous immunity is a mechanism by which immunological memory within an individual, developed in response to a previous infection, plays a role in the immune response to a subsequent unrelated infection. In murine studies, heterologous immunity facilitated by cross-reactive CD8 T-cell responses can mediate either beneficial (protective immunity) or detrimental effects (e.g. enhanced lung and adipose immunopathology and enhanced viral titers) (Selin et al., 1998; Chen et al., 2001; Welsh and Selin, 2002; Nie et al., 2010; Welsh et al., 2010). Protective heterologous immunity results in enhanced clearance of virus during a subsequent infection with an unrelated pathogen. Such is the case when mice are immunized with lymphocytic choriomeningitis virus (LCMV) and subsequently challenged with Pichinde virus (PV) or vaccinia virus (VACV) (Selin et al., 1998). However, heterologous immunity may also mediate enhanced immunopathology as mice immunized with influenza A virus (IAV) and challenged with LCMV show increased viral titers and enhanced lung immunopathology (Chen et al., 2003).
The role heterologous immunity plays during infection is not limited to the murine system. In fact, there have now been several reports of enhanced immunopathology due to heterologous immunity during human infections, involving viruses such as IAV, Epstein-Barr Virus (EBV), hepatitis C virus (HCV), and dengue virus (DENV) (Mathew et al., 1998; Wedemeyer et al., 2001; Acierno et al., 2003; Nilges et al., 2003; Clute et al., 2005; Urbani et al., 2005). Interestingly, in all reported cases in humans, heterologous immunity mediated enhanced immunopathology.
Upon infection with EBV the clinical presentation can range from asymptomatic to severe, occasionally fatal, acute infectious mononucleosis (AIM) (Crawford et al., 2006b; Luzuriaga and Sullivan, 2010) which is marked by a massive CD8 lymphocytosis. This lympho-proliferative effect in AIM was shown to be partially mediated by reactivation of cross-reactive IAV-M1 58-66 (IAV-GIL) specific CD8 memory T-cells in HLA-A2 patients reacting to the EBV-BMLF1 280 (EBV-GLC) epitope (Clute et al., 2005).
Interestingly, EBV infects ~90% of individuals globally by the third decade of life, establishing a life-long infection (Henle et al., 1969). However, it is unknown why 5-10% of adults remain EBV-sero-negative (EBV-SN), despite the fact that the virus infects the vast majority of the population and is actively shed at high titers even during chronic infection (Hadinoto et al., 2009). Here, we show that EBV-SN HLA-A2+ adults possess cross-reactive IAV-GIL/EBV-GLC memory CD8 T-cells that show highly unique properties. These IAV-GIL cross-reactive memory CD8 T-cells preferentially expand and produce cytokines to EBV antigens at high functional avidity. Additionally, they are capable of lysing EBV-infected targets and show the potential to enter the mucosal epithelial tissue, where infection is thought to initiate, by CD103 expression. This protective capacity of these cross-reactive memory CD8 T-cells may be explained by a unique T-cell receptor (TCR) repertoire that differs by both organization and CDR3 usage from that in EBV-seropositive (EBV-SP) donors.
The composition of the CD8 T-cell repertoire is a dynamic process that begins during the stochastic positive selection of the T-cell pool during development in the thymus. Thus, upon egress to the periphery a naïve T-cell pool, or repertoire, is formed that is variable even between genetically identical individuals. This T-cell repertoire is not static, as each new infection leaves its mark on the repertoire once again by stochastically selecting and expanding best-fit effectors and memory populations to battle each new infection while at the same time deleting older memory CD8 T-cells to make room for the new memory cells (Selin et al., 1999). These events induce an altered repertoire that is unique to each individual at each infection. It is this dynamic and variable organization of the T-cell repertoire that leads to private specificity even between genetically identical individuals upon infection with the same pathogens and thus a different fate (Kim et al., 2005; Cornberg et al., 2006a; Nie et al., 2010). It is this private specificity of the TCR repertoire that helps explain why individuals with the same epitope specific cross-reactive response, but composed of different cross-reactive T-cell clones, can either develop AIM or never become infected with EBV.
Our results suggest that heterologous immunity may protect EBV-SN adults against the establishment of productive EBV infection, and potentially be the first demonstration of protective T-cell heterologous immunity between unrelated pathogens in humans. Our results also suggest that CD8 T-cell immunity can be sterilizing and that an individual’s TCR repertoire ultimately determines their fate during infection.
To conclusively show that heterologous immunity is actively protecting EBV-SN adults from the establishment of a productive EBV infection, one would have to deliberately expose an individual to the virus. Clearly, this is not an acceptable risk, and it could endanger the health of an individual. A humanized mouse model could allow one to address this question.
However, before we can even attempt to address the question of heterologous immunity mediating protection from EBV infection in humanized mice, we must first determine whether these mice can be infected with, and build an immune response to the two viruses we are studying, EBV and IAV. We show here that these mice can indeed be infected with and also mount an immune response to EBV. Additionally, these mice can also be infected with IAV. However, at this time the immune responses that are made to these viruses in our established humanized mouse model are not substantial enough to fully mimic a human immune response capable of testing our hypothesis of heterologous immunity mediating protection from EBV infection.
Although the immune response in these mice to EBV and IAV infection is not suitable for the testing of our model the data are promising, as the humanized mouse model is constantly improving. Hopefully, with constant improvements being made there will be a model that will duplicate a human immune system in its entirety.
This thesis will be divided into 5 major chapters. The first chapter will provide an introduction to both general T-cell biology and also to the role of heterologous immunity in viral infection. The second chapter will provide the details of the experimental procedures that were performed to test our hypothesis. The third chapter will describe the main scientific investigation of the role of heterologous immunity in providing natural resistance to infection in human subjects. This chapter will also consist of the data that will be compiled into a manuscript for publication in a peer-reviewed journal. The fourth chapter will consist of work performed pertaining to the establishment of a humanized mouse model of EBV and IAV infection. The establishment of this model is important for us to be able to show causation for protection from EBV infection mediated by heterologous immunity.
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Wang, Lili. "The role of T cell immunity in natural influenza A infection in a UK cohort : flu watch." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669930.
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A novel influenza A virus bearing the characteristics of high virulence, the ability to infect humans and transmit from human to human, such as the pandemic influenza of 1918, could lead to millions of deaths. The 2009 influenza pandemic demonstrated that a novel influenza A virus could spread globally in a few months despite the availability of modern comprehensive surveillance systems and systemic prevention and control measurements. Novel pandemic strains that could occur naturally or be created in laboratory, pose a serious threat to public health. Current available vaccines are capable to induce neutralizing antibodies against the viral surface antigen hemagglutinin (HA), which provide sterilizing immunity by blocking infection. However this antibody protection is serotype specific and therefore offers limited or no protection against a serologically distinct influenza virus. An alternative vaccine approach is the induction of cross-protective T cell immunity, directed at influenza A conserved internal proteins which could potentially offer broad protection against different influenza strains in humans. This approach may complement antibody-inducing vaccines and greatly enhance the protective efficacy of influenza vaccines. This study builds on previous evidence derived from animal models and human experimental challenge studies, to demonstrate the heterotypic T cell immunity in the context of natural influenza A infection in humans. Pre-existing influenza A specific T cell immunity was quantified by human IFN-γ ELISpot assay and was detectable in over 70% of Flu Watch participants. Nucleoprotein was the most immunodominant viral protein; and the most potent viral protein in eliciting influenza A specific CD8+ T cells. The nucleoprotein specific T cells exhibited high level of cross reactivity to the 2009 pandemic influenza and reduced the occurrence of nasal viral shedding in the absence of antibody immunity, following acquisition of pandemic influenza infections. This study provides evidence to support the development of a T cell based influenza vaccine, and provides important evidence to empower future studies of this kind.
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Batista, Mariana Dias. "Avaliação de aspectos inatos e adaptativos do sistema imune na psoríase: análise fenotípica e funcional de células natural killer e células T." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-13032013-170151/.
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INTRODUÇÃO: A psoríase é doença inflamatória hiperproliferativa da pele, na qual mecanismos imunológicos são cruciais para o processo patogênico. O marcador CD57 denota inabilidade de replicação e imuno-senescência de células T CD8+, e sua expressão foi demonstrada em diversas condições inflamatórias. CD57 também pode ser expresso por células natural killer (NK), nas quais é considerado marcador de maturidade, por ser em geral adquirido pelas formas mais diferenciadas CD56+CD16+. A expressão de CD57 e outros receptores de células NK não foi amplamente investigada na psoríase. OBJETIVOS: Este estudo buscou examinar o fenótipo de células NK em biópsias de pele e células mononucleares do sangue periférico (CMSP) de pacientes com psoríase em relação a controles sadios. Este estudo investigou também o fenótipo e características funcionais de células T isoladas da pele lesional e não afetada de pacientes com psoríase. MÉTODOS: Foram isoladas células NK dos subtipos CD56+CD16- e CD56+CD16+ de pele lesional, não afetada e CMSP de pacientes com psoríase, comparadas com pele normal e CMSP de controles sadios. A expressão de CD57, NKG2A e NKG2C foi determinada nesses subtipos de células por citometria de fluxo. Células T CD4+ e CD8+ foram isoladas da pele lesional e não afetada de pacientes com psoríase, e a expressão de CD57 foi avaliada. Características funcionais de células T foram estudadas através da análise da secreção de diversas citocinas inflamatórias (IL-17A, IFN-\", IL-2, IL-33, TNF- #, IL-21, IL-22 and IL-27) produzidas por células T CD4+ e CD8+ isoladas por sorting celular, a partir de amostras de pele lesional e não afetada de pacientes com psoríase. RESULTADOS: Células NK isoladas das lesões de psoríase apresentaram um fenótipo particular, caracterizado por baixa expressão de CD57 e alta expressão de NKG2A na pele lesional e não afetada em relação aos controles. Em relação às células T, encontrouse frequência de células T CD4+CD57+ e CD8+CD57+ significativamente maior na pele não afetada em relação à pele lesional de pacientes com psoríase. Células T CD4+ isoladas por sorting celular a partir de amostras de pele lesional produziram níveis maiores de IL-17A, IL-22 e IFN-\" em relação às amostras de pele não afetada. Células T CD8+ isoladas da pele lesional secretaram maiores níveis de IL-17A, IFN-\", TNF-# e IL- 2 em relação à pele não afetada. CONCLUSÕES: Esses dados sugerem que células NK presentes nas lesões de psoríase apresentam fenótipo imaturo, que foi previamente associado a maiores capacidades funcionais, e poderiam ser implicadas na patogênese da psoríase. Em relação às células T, as características fenotípicas sugerem menor sobrevivência de células com baixa capacidade replicativa na pele lesional, pelo ambiente inflamatório local ou pelo alto turnover celular da psoríaseINTRODUCTION: Psoriasis is a hyper-proliferative inflammatory disease of the skin in which immunological mechanisms play a direct role in disease pathogenesis. CD57 is a marker of replicative inability and immunosenescence on CD8+ T cells and its expression is increased in a number of inflammatory conditions. CD57 is also expressed by NK cells and is considered a marker of NK cell maturity, being acquired by more differentiated CD56+CD16+ NK cells. The expression of CD57 and other NK cell markers in psoriasis has not been thoroughly investigated. OBJECTIVES: This study sought to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells (PBMC) from patients with psoriasis and healthy controls. We also investigated the phenotype and functional characteristics of T cells from psoriasis patients, comparing lesional and unaffected skin. METHODS: CD56+CD16- and CD56+CD16+ NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A, and NKG2C was assessed by flow cytometry. CD57 expression was also determined on T cells from lesional and unaffected skin by flow cytometry. We assessed functional characteristics of T cells by evaluating the secretion of several inflammatory cytokines (IL-17A, IFN-\", IL- 2, IL-33, TNF-#, IL-21, IL-22 and IL-27), from cell-sorted purified CD4+ and CD8+ T cells isolated from lesional and unaffected skin of psoriasis patients, by multiplex assays. RESULTS: NK cells in psoriasis skin lesions exhibited a distinct phenotype, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. In relation to T cells, we observed that the frequency of CD57+CD4+ and CD57+CD8+ T cells was significantly increased in unaffected skin of psoriasis patients compared to lesional skin. Sorted CD4+ T cells from psoriasis lesional skin produced higher levels of IL-17A, IL-22 and IFN-\" compared to unaffected skin. CD8+ T cells isolated from lesional skin produced higher levels of IL- 17A, IFN-\", TNF-# and IL-2 compared to unaffected skin. CONCLUSIONS: These data suggest that NK cells in psoriasis lesions exhibit an immature phenotype, that has been previously associated with higher functional abilities, and could implicate NK cells in psoriasis pathogenesis. For T cells, the findings of this study suggest lower survival of cells with low replicative ability in lesional skin, due to the local inflammatory environment or to the high cellular turnover in psoriasis
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Godoy, Ramirez Karina. "Flow cytometric methods for assessment of cell-mediated immune responses /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-409-0/.
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Rezvany, Mohammad Reza. "Natural specific T cell immunity in patients with B-cell chronic lymphocytic leukaemia (B-CLL) : (a clinical and immunological study) /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4841-0/.
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Papenfuss, Tracey L. "Hormones and dendritic cells influences on the initiation of the autoimmune disease experimental autoimmune encephalomyelitis /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1173196704.
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Judge, Chelsey J. "IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387.
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Northfield, John. "Aspects to T-cell phenotype during infection with HIV, CMV and Hepatitis C virus." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:283098ce-e24d-4099-8826-07dcc75381f2.
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This work concerns itself with understanding the organisation of cellular immune responses to three major human pathogens - HIV, CMV and Hepatitis C (HCV). Each was studied to form three projects, each undertaken with a different approach - arrived at independently - and largely owing their origins to opportunity and circumstance as much as design. Each project led to exploration of a particular aspect of T-cell phenotype (that is the expression of particular molecular markers on T-cells) and its’ broader biological significance. I found that T-cell phenotype was strongly linked to the magnitude of T-cell responses (CMV) and the ability of T-cells to control infection (HIV). Finally I explored the significance of expression of a molecule known as CD161 on the surface of HCV specific CD8+ T-cells, indicating a phenotype of T-cell that may not follow the ‘normal rules’ applicable to T-cells in general.
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May, Kenneth F. "T cell costimulation in anti-tumor immunity and autoimmunity." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085004772.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xv, 178 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 May 20.
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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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Fowler, Sanna Margrethe. "The role of CD4'+ T cells in mucosal immunity." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393226.
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Lei, Hong. "Human natural regulatory T cells subsets." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16958.
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Regulatorische T-Zellen (Treg) eröffnen neue immuntherapeutische Wege zur Kontrolle unerwünschter Immunreaktionen, jedoch wirft die Heterogenität dieser Zellen die Frage auf, welche Treg-Population für die klinische Anwendung. Darauf basierend werden in dieser Arbeit drei Fragestellungen bearbeitet: i) Bestimmung der Häufigkeit von Tregs und deren Subpopulationen in verschiedenen Altersgruppen bei Empfängern einer Organtransplantation (Tx) und einer gesunden Kontrollgruppe; ii) Vergleich der Suppressorkapazität verschiedener Treg-Populationen und in vitro-Expansion der Zellen unter Erhaltung ihrer Funktionalität; iii) Klärung der Differenzierungsmerkmale von Tregs und deren Verknüpfung mit konventionellen T-Zellen (Tconv) mittels Analyse des T-Zell-Rezeptor- (TCR) Repertoires. Sowohl bei gesunden Probanden als auch bei Tx-Empfänger konnte eine altersabhängige Verschiebung von naiven (TregN) hin zu dominant zentralen Gedächtnis-Zellen (TregCM) beobachtet werden, Treg von Tx-Empfängern hatten mehr Effektor-Memory-Zellen (EM) und sie waren mehr aktiviert. In Bezug auf die Kontrolle der frühen Tconv zeigen TregCM eine erhöhte Suppressorkapazität im Vergleich zu TregN. Außerdem sind im Gegensatz zu TregN nur TregCM dazu in der Lage, Apoptose bei Responderzellen zu induzieren. Der Grund hierfür könnte in der stärkeren Expression von CTLA-4 auf TregM liegen. Die Expansionskultur führte zur phänotypischen Veränderung der TregN, deren Umwandlung in TregCM mit einer verbesserten Suppressoraktivität verbunden ist. Die Daten legen nahe, dass das Expandieren mit gesamt Treg für die Adoptive-Treg-Therapie optimal sind, da sie der größte Anteil von ihnen die hochpotenten TregCM sind. TCR-Studien mittels Next Generation Sequencing zeigen weiter, dass TregM aus TregN entstehen, anstatt aus Tconv, in einem Antigen-gesteuerten Prozess. Diese Daten belegen erstmalig neue Erkenntnisse hinsichtlich der Unterschiede der TCR-Repertoires von TregM und Tconv beim Menschen.Regulatory T cells (Treg) offer new immunotherapeutic options to control undesired immune reactions, but the heterogeinetiy of Treg raises the question which Treg population should be used for clinical translation Thus, this project involves three main parts: i) investigating Treg frequency and subsets distribution with age in healthy donors and transplant (Tx) patients; ii) comparing the suppressive capacity of Treg subsets and expanding them in vitro without losing functionality; iii) clarifyjing the differiation relationship of Treg subsets and their relation to conventional T cells (Tconv) by T cell receptor (TCR) repertoire analysis. From both healthy donors and Tx patients, an age-dependent shift from naïve Treg (TregN) to the dominant central-memory Treg (TregCM) was observed,; However,Treg in Tx patients contained more effector-memory EM cells, , and they were pre-activated due to the exposure to allo antigens,. Regarding control of early Tconv activation, TregCM showed enhanced suppressive capacity compared to TregN; furthermore, only TregCM could induce apoptosis of responder cells while TregN could not, which may result from thehigherexpression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) on TregM. Following in vitro expansion of the Treg subsets, however, TregN converted mainly into TregCM phenotype with enhanced suppression activity. The poor proliferation capacity of TregEM might indicate EM as the terminal differential stage. These data suggest that expansion with total Treg is optimal for adoptive Treg therapy as the majority of them are the highly potent TregCM. Lastly, TCR repertoire study by next generation sequencing (NGS) indicate that TregM derived from TregN rather than Tconv in an antigen-driven process. The highest similarity of the TCR repertoires was observed between TregCM and TregEM. These data reveal new insights for the first time into the distinct TCR repertoires of Treg subsets and Tconv in human by NGS technology.
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Graham, Christine Marian. "Anti-viral immunity : helper T cells in influenza virus infection." Thesis, Oxford Brookes University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444320.
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Mahon, Bernard Patrick. "The role of CD4'+ T cells in immunity to poliovirus." Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385009.
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Reed, Jennifer. "Interferon-gamma increases CD4+ T cell survival and proliferation." Click here for download, 2006. http://wwwlib.umi.com/cr/villanova/fullcit?p1432655.
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Rigby, Mark R. "R T 6: a Bifunctional Protein of Regulatory T Cells." eScholarship@UMMS, 1995. http://escholarship.umassmed.edu/gsbs_diss/283.
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The immune system is a complex network of cells and molecules that is a powerful and necessary defense mechanism to protect the host from pathogens. When this system is non-functional or dysregulated, the host is susceptible to takeover or attack against self, both with often lethal sequelae. Over the past century remarkable advances have been made in understanding how the immune system functions and how to manipulate this knowledge for human benefit. One strategy used to understand immune system function is to determine how the activity of immune system cells is modulated by the proteins these cells express on their surface.
One rat T cell surface protein which was originally identified with antibodies almost two decades ago is the rat T cell alloantigen, RT6. During the intervening time enormous progress has been made in understanding the function of RT6+ T cells in normal and abnormal immune responses. In addition, during this time the characterization of RT6 genes, proteins, and homologues has occurred. One characterization of RT6 that is enigmatically missing is the function of this molecule. With this information it would be possible to determine how this molecule modulates T cell function. Therefore this project set out to begin to functionally characterize RT6 proteins. Part 1 of this project set out to determine if cell-surface RT6 proteins, like some other T cell surface proteins, could mediate T cell activation. Part 2 of this project was based on the recent observation that RT6 is homologous to NAD-catabolizing enzymes, and it was investigated whether RT6 proteins have ADP-ribosyltransferase activity.
In Part 1 of this work it is demonstrated that cell-surface RT6 proteins are capable of delivering activation signals to T cells. Crosslinking cell-surface RT6 with antibodies potentiates the ability of PMA treated T cells to proliferate in response to the T cell growth factors IL-2 and/or IL-4. Crosslinking RT6 on these cells increases the surface expression of IL-2 receptors, suggesting that RT6-mediated signals selectively enhance growth factor receptor expression. This work also investigated the mechanism through which RT6 may deliver its signal. It is demonstrated that RT6 proteins are physically associated with five other proteins, including the src family tyrosine kinases p56lck and p60fyn. This work also suggests a novel mechanism to regulate T cell signaling by accessory molecules, since PKC activation causes qualitative and quantitative changes in the proteins physically associated with RT6. This work indicates that cell-surface RT6 is capable of delivering an accessory T cell activation signal. Therefore, RT6 proteins may be involved in vivo with the activation and proliferation of RT6+ T cells.
Previous work in another laboratory has demonstrated that the RT6.2 protein possesses NAD glycohydrolase activity and indicated that RT6 proteins share overall sequence homology with ADP-ribosyltransferases. In Part 2 of this work, RT6 proteins are shown to possess NAD:arginine ADP-ribosyltransferase activity. ADP-ribosylation of proteins is a modification known to affect cell signaling and function. It is further demonstrated in this work that the substrate for RT6, extracellular NAD, inhibits T cell proliferation in a dose- and stimulus-dependent manner. Taken together, these studies suggest that through their enzymatic activities RT6 proteins modulate T cell activity.
This work is the first to demonstrate that RT6 has two, possibly separate, functional characteristics. RT6 can therefore be described as a bifunctional T cell surface protein. RT6+ T cells play critical roles in regulating immune system responses in health and disease. Because of these functional studies on RT6 proteins, it can now be investigated how RT6 proteins may modulate T cell responses in different immunological situations. Thus, this work will provide the foundation to determine if and how RT6 proteins modulate immune system function in health and disease.
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Zheng, Ying. "A complementary activation of peripheral NK cell immunity in EBV related nasopharyngeal carcinoma." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B34605162.
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Kurioka, Ayako. "Mucosal associated invariant T cells and CD161 expressing natural killer cells." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:f994e661-d241-4a1c-ac56-b6bea73346ac.
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Mucosal-associated invariant T (MAIT) cells are a population of innate-like lymphocytes within the gut, liver and blood, expressing a semi-invariant T cell receptor (TCR) and high levels of the C-type lectin-like receptor, CD161. These cells recognise a metabolite of the microbial riboflavin synthesis pathway, presented by the highly conserved Major Histocompatibility Complex (MHC) class I-related protein, MR1, and are critical for the control of bacterial infections. The factors regulating the broad effector functions of MAIT cells have not been fully investigated. Utilising a novel flow cytometric killing assay, MAIT cells were shown here to require the induction of a cytotoxic phenotype through bacterial stimulation to efficiently kill target cells. Further in depth phenotypic analysis highlighted a distinct non-cytotoxic subset of CD4+ MAIT cells, with an altered cytokine-producing capacity, enriched within lymphoid tissues. Investigation into the potential role of these cells in psoriatic diseases revealed that MAIT cells within the synovial fluid of psoriatic arthritis patients are potently activated with increased IL-17 production, their frequency correlating with measures of clinical activity. MAIT cells also have an innate-like responsiveness to cytokines, a feature originally attributed to Natural Killer (NK) cells. Microarray analysis and mass cytometry experiments demonstrated that CD161 marks immature NK cells that have retained this ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus (CMV)-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. Thus, CD161 marks cells with innate-effector functions both in T cells and NK cells.
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Nylén, Susanne. "A role for NK cells in innate immunity against human leishmaniasis /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-605-7/.
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Zettervall, Carl-Johan. "Signaling pathways in the activation and proliferation of Drosophila melanogaster blood cells." Doctoral thesis, Umeå : Umeå centrum för molekylär patogenes (UCMP), 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-513.
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Forsberg, Göte. "Innate and adaptive immunity in childhood celiac disease /." Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-874.
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Malick, Adrien Paul. "Tumor-induced immunosuppression: Contribution of a high molecular weight inhibitor and Prostaglandin E2." Diss., Virginia Polytechnic Institute and State University, 1987. http://hdl.handle.net/10919/53639.
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A heat-stable soluble inhibitor of T cell proliferation was demonstrated in splenic and peritoneal macrophage (Mφ) culture supernatants. Concentrated supernatants were prostaglandin E₂ (PGE₂)-free and yet inhibited proliferation in the mixed lymphocyte reaction (MLR) and mitogen assays. The high mw inhibitory factor was apparently >67 kd, as shown by S-200 Sephacryl chromatography and gel electrophoresis. DEAE-Cellulose chromatography suggested that the pl of the inhibitory factor was < 7.7. lsoelectric focusing revealed that the Mφ-mediated inhibitory activity differed in charge, with a pl of 6.5-7.6 for normal hosts and 4.0-6.0 for tumor bearing hosts (TBH). Normal and TBH Mφ supernatants showed different hydroxylapatite fractionation, with the latter being resistant to proteolytic enzymes but sensitive to neuraminidase. Lectins such as wheat germ agglutinin, concanavalin A, Ricin communi: and Bandeirea simplicifolia were not useful in affinity purification of the high mw inhibitory monokine. Sugar-BSA conjugates suggested that inhibitory activity was vested in a terminal ßl,4 linked galactose. The inhibitory activity was apparently hydrophobic and heat·stable, but heat-stability was lost if supernatants were boiled at an acidic pH. The high mw monokine inhibited the proliferation of P388D₁ and A4A cells, but enhanced the proliferation of BW 5147.3 cells. Time course addition to the MLR revealed that PGE; may be required for inhibitory activity to be manifested early (0 and 24 hr) but not if the high molecular weight (mw) inhibitor was added late (>48 hr). Indomethacin blocked activity of the inhibitory factor early in the MLR using normal host T cells and augmented the proliferation of TBH T cells in the MLR. Both normal and TBH Mo supernatants suppressed the generation of interleukin 2 but with a dose- and time·dependent difference. Cell cycle analysis of mitogen- stimulated cells revealed that TBH MPh. D.
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Kamel, Fatemah Omar. "Invariant natural killer T cells in multiple sclerosis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/40281.
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Invariant natural killer T (iNKT) cells are a subpopulation of lymphocytes that express both a CD1d-restricted αβ T cell receptor (TCR) and NK cell markers. iNKT cell perturbations are implicated in a wide variety of autoimmune diseases including Multiple Sclerosis (MS). Our results confirmed a significant reduction in the percentage of iNKT cells in MS patients with respect to healthy donors. In order to understand the immunological significance of iNKT cell reduction in MS, we aimed to define iNKT subsets in a cohort of MS patients of different disease types, Clinically Isolated Syndrome patients (CIS) and patients on different treatments by means of multiparameter flow cytometry and TCR analysis. TCR analysis showed that Vα24 CDR3 region is highly conserved between healthy controls and MS patients, while TCR Vβ11 CDR3 region in iNKT cells of MS patients appeared constrained relative to the pool of cells in healthy controls. As activation, differentiation and maturation processes can be involved in the reduced frequency of iNKT cells, we investigated the role of CD25, CD62L, CD69, CD161 and CD195. Initial observation suggested that co-expression of CD25 and CD161 on iNKT cells is significantly higher in MS patients compared to healthy controls, while CD161 alone is decreased, suggesting that a subpopulation of iNKT cells might be acting as 'regulatory subsets' in MS. Because many genetic studies have shown that specific killer cell immunoglobulinlike receptor (KIR) family have a strong association with MS, we evaluated the expression of KIR2DL1/S1, KIR2DL2/L3 and KIR3DL1 on iNKT cells. Our results showed that expression of KIR2DL1/S1 and KIR3DL1 is lower in progressive MS patients compared to healthy controls. RRMS untreated patients have lower expression of both KIR2DL2/L3 and KIR3DL1 than patient treated with Natalizumab, while the contrary is true when looking at expression of KIR2DL1/S1. All together our data showed that perturbation of iNKT cells is associated with expression of specific surface receptors, thus defining subsets of iNKT cells that might be related to progression of disease or used as disease markers.
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Martin, Matthew David. "Naive and memory CD8 T cell responses after antigen stimulation in vivo." Thesis, University of Iowa, 2011. https://ir.uiowa.edu/etd/1246.
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The extent to which the progeny of one primary memory CD8 T cell differs from the progeny of one naïve CD8 T cell of the same specificity remains an important question. In order to explore cell autonomous functional differences between naïve and memory CD8 T cells that are not influenced by differences in the priming environment, an experimental model has been developed in which physiological numbers of both populations of cells were co-transferred into naïve host before antigen-stimulation. Interestingly, naïve CD8 T cells expand in numbers more than primary memory CD8 T cells after various infections or immunizations. The intrinsic ability of one naïve CD8 T cell to give rise to more effector CD8 T cells than one memory CD8 T cell is independent of the number of primary memory CD8 T cells present in vivo. The sustained proliferation of primary, but not the increased death of secondary effectors was shown to contribute to the differences in the observed magnitudes of expansion. In addition, longitudinal analysis of primary and secondary CD8 T cell responses revealed that the ability of naïve CD8 T cells to generate long-lived progeny (`memory generation potential') is better than for primary memory CD8 T cells despite the differences in overall kinetics of both responses after infection. Taken together, the data presented here revealed previously unappreciated differences between naïve and memory CD8 T cells and will help further define the functional potential for both cell types.
The goal of immunization is to generate memory CD8 T cells of sufficient quality and quantity, and it has been shown that the naïve to primary memory CD8 T cell differentiation in vivo is controlled, at least in part, by the amount and duration of inflammation present early after the initiation of the response. In experiments where naïve CD8 T cells were co-transferred with increasing numbers of primary memory CD8 T cells, we observed a negative correlation between the number of primary memory present and the magnitude of primary CD8 T cell responses. Interestingly, the conversion of newly recruited (either TCR-Tg or endogenous) primary CD8 T cells into CD8 T cells with the phenotype (CD62Lhi, CD27hi) and function (tissue distribution, Ag-driven proliferation, cytokine production) of long-term memory was facilitated when they were primed in the presence of memory CD8 T cells of the same or unrelated specificity. Therefore, these data suggest that the presence of anti-vectorial immunity will not necessarily decrease the efficacy of CD8 T cell vaccination since newly recruited CD8 T cells, despite their decreased magnitude of expansion, might differentiate into functional memory cells faster.
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Hansson, Lotta. "Natural and induced idiotype immunity in patients with multiple myeloma /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-820-3/.
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Hu, Yong. "Altered T Cell-Mediated Immunity and Infectious Factors in Autism." DigitalCommons@USU, 2000. https://digitalcommons.usu.edu/etd/6846.
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Three major questions were addressed in this dissertation: 1)Do immune abnormalities associated with autism primarily alter CD4+ T cell-mediated or humoral immune responses? 2) Are specific T cell clones expanded in autism? 3) Which, if any, infectious agents play a role in autism?
CD4+ T cell-mediated (Th1) or humoral (Th2) immune responses can be distinguished on the basis of the cytokines expressed. CD4+ T-cells secrete interleukin type 2 (IL-2) and interferon-γ, whereas a Th2 response is associated with secretion of interleukin type 4(IL-4). mRNA extracted from peripheral blood mononuclear nuclear cells (PBMC) showed significantly increased levels of IL-2 and interferon-γ expression in 24 autistic subjects relative to 19 normal controls. IL-4 mRNA was undetectable in the same group of autistic subjects. These results indicate that a CD4+ T cell-mediated immune response is associated with autism.
The expression of V-β chain mRNA was used as a marker or particular T cell clone expression. The expression of V-β 13 was significantly elevated in the study group of 11 autistic subjects, but not in 9 normal subjects. This suggests that T cell-mediated autoimmunity is a factor in the disease. Two types of human leukocyte antigens (HLA) alleles, DR4 and DR1, are associated with autism. The association between V-β 13 expressing T cell clones and autism was shown even more strongly in the subgroups expressing HLA DR4 or DR1. This result suggests a link between antigen presentation by HLA DR4 or DR1 and expansion of V-β 13 T cell clones.
The potential involvement of pathogens suspected to trigger autism was investigated by examining T cell proliferation responses to peptide epitopes. As a group, the 24 autistic subjects did not show a decreased response to peptides derived from rubella virus, influenza A virus, herpes simplex virus type 1, cytomegalovirus, and Clostridium tetani. Another model of autism postulates that autism is induced by pathogens that possess epitopes identical to the hypervariable region 3 (HVR-3) of the HLA DR4 or DR1 alleles. Two antigens derived from the Escherichia coli dna J protein and the Epstein-Barr virus glycoprotein 110 peptides that contain sequences identical to the HVR-3 of the DR4 and DR1 alleles were examined for their ability to induce T cell proliferation in autistic and normal subjects. No effect of the DR4 or DR1 alleles on the response to these two antigens was detected. Therefore, both types of results do not support the model of immune tolerance in autism. However, average T cell proliferative activity was significantly lower in the same autistic subjects. This confirms many prior reports that reduced T-cell responses may shape susceptibility to autism.
Further understanding of how immune abnormalities and infectious agents lead to autism should guide development of preventative and therapeutic strategies for this disease. (152 pages)
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Li, Peng. "Reprogramming of T cells to natural killer-like cells upon BCL11B deletion." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609198.
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Heil, Luke. "THE ROLE OF CD8 T CELL IMMUNODOMINANCE AND REGULATORY T CELLS IN NEONATAL IMMUNITY TO INFLUENZA VIRUS." UKnowledge, 2019. https://uknowledge.uky.edu/microbio_etds/22.
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Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed for conferring protection to multiple influenza virus strains, but if T cell vaccines will be used in infants and adults, neonates must be able to respond to the same T cell antigens as adults. Mouse pups responded to influenza virus peptide PA224-233 but not NP366-374 during influenza virus infection in contrast to the codominant adult response. Mice infected as pups also generated diminished T cell memory compared to mice infected as adults and displayed skewed immunodominance during secondary infection. Adult bone marrow derived dendritic cells (BMDCs) improved viral clearance when loaded with influenza virus and promoted NP366-374-specific CD8+ T cell responses in infected pups. BMDC peptide vaccination could stimulate PA224-233-specific but not NP366-374-specific CD8+ T cell responses in pups, but, PA224-233 vaccination offered no protection to pups during lethal infection. These data suggest that altered immunodominance must be considered when stimulating CD8+ T cell responses in adults and neonates.
Immaturity and active suppression of immune responses are both factors in neonatal vulnerability to disease. Specifically, active suppression of neonatal immunity by regulatory T cells (Tregs) has been proposed as a driving factor in diminished neonatal immunity, but removing these cells can compromise viral defense or increase deleterious inflammation. Mice that lacked Tregs displayed compromised anti-influenza antibody responses and decreased lymph node responses during influenza virus infection. A high proportion of pup Tregs also expressed Gata3. Transgenic pups with a Treg specific Gata3 knockout displayed an increase in Tbet expression in both conventional and regulatory T cells and an increase in IFNγ producing CD4+ T cells in the lungs during infection. These data suggest that Tregs are required for effective humoral responses to influenza virus and that Gata3 expression influences Treg suppressive function in neonates.
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Pynn, Michael. "Obesity and asthma : the role of innate immunity, adipokines and regulatory T cells." Thesis, Swansea University, 2014. https://cronfa.swan.ac.uk/Record/cronfa42704.
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Introduction: Obesity and asthma are associated but the mechanism is poorly understood. Enhanced systemic inflammation may underlie the obesity-asthma paradigm. Although there is good mechanistic data that obesity augments the immune response as well as promoting immune dysregulation by reducing regulatory T cell numbers, there is little work relating this to obesity and asthma. Methods: A case-control study examined 6 groups of pre-menopausal women (n=84); non-obese, f overweight and obese individuals with and without asthma. Measures of adiposity and lung function I were taken and peripheral blood collected during the first 7 days of the menstrual cycle. Innate immune parameters measured included: full blood count and differential; chemiluminescence recorded whole blood reactive oxygen species; neutrophil related cytokines; neutrophil and i monocyte activation markers by flow cytometry, and LPS induced whole blood cytokine responses. Insulin resistance, adipokine levels and free fatty acid levels were recorded. Dendritic cell and lymphocyte subtypes including FoxP33+ regulatory T cells (Tregs) were quantified by flow cytometry I and PHA-induced cytokine responses measured in whole blood. Results: Obesity and asthma appeared to have synergistic effects with regards to circulating I neutrophil count, plasma IL-6 and leptin with obese asthmatics having the highest levels. Reactive I oxygen species production followed a similar trend. Increasing BMI within asthmatics was associated f with a reduction in eosinophils and myeloid dendritic cells, and increased PHA-induced IFNy. Obesity I across the entire study group was associated with increased neutrophil counts and neutrophil P related cytokines, reduced FoxPS3+Tregs and increased PHA-induced IL-17 response. Conclusions: Systemic changes in immunity occur in obesity and asthma; some of these are additive. Within asthmatics, obesity is associated with responses suggesting T helper 1 (Th1) rather than Th2 bias. Obesity-associated systemic changes in immunity might encourage a loss of immune tolerance. These findings suggest that obesity might mediate its effects in asthma through systemic inflammatory mechanisms.
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Saunders, Margaret. "Analysis of immune responses to transformed cells in vitro." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481435.
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Mosolits, Szilvia. "Natural and induced immunity aginst the tumour-associated antigen, Ep-CAM /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-752-5.
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Morton, Angela Mary Young. "Investigation of T cell signalling events regulating immunity and tolerance in vivo." Thesis, Connect to e-thesis, 2008. http://theses.gla.ac.uk/59/.
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Thesis (Ph.D.) - University of Glasgow, 2007.Ph.D. thesis submitted to the Division of Immunology, Infection and Inflammation, Faculty of Medicine, University of Glasgow, 2007. Includes bibliographical references.
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Puleston, Daniel. "The role of autophagy in CD8plus T cell immunity." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:6cc5b853-4899-4de2-8924-71f7ee0659a1.
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Zheng, Ying, and 鄭盈. "A complementary activation of peripheral NK cell immunity in EBV related nasopharyngeal carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B34605162.
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Ali, Ayad. "Natural killer cells dictate outcomes of infection by orchestrating innate and adaptive immunity." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1624914672655234.
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Chow, Michael T. "Functional characterization of H2-M3-restricted CD8⁺ T cells in innate and adaptive immunity." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/20596.
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The outcome of many host immune responses to perturbations caused by pathogenic infections is dependent on the coordinated actions between innate and adaptive immune cells. Despite the seemingly clear distinction immune cells belongs either to the innate or adaptive immune system, CD8⁺ T cells that exhibit properties attributed to both compartments of the immune system exist. Specifically, a subset of MHC class Ib molecules, H2-M3, preferentially binds to and presents formylated-peptides to CD8⁺ T cells resulting in their rapid expansion, quick production of cytokines, and provision of cytolytic protection against bacterial infections. The work in this thesis is focused on the discovery and characterization of the immunoregulatory potential of H2-M3-restricted T cells. Specifically, the activation of H2-M3-restricted T cells provided early signals for the efficient priming of antigen-specific CD4⁺ T cell responses following immunization, which translated to augmented CD4⁺ T cell numbers during the acute, effector, and memory phase following bacterial infection. Augmented CD4⁺ T cell responses generated with additional signals derived from activated H2-M3-restricted T cells also significantly increased primary antigen-specific responses by conventional MHC class Ia-restricted CD8⁺ T cells. Importantly, a second MHC class Ib molecule, Qa-1, whose human equivalent is HLA-E, was also identified to augment CD4⁺ T cell responses, in vivo. The ability for H2-M3-restricted T cells to provide help to the helper CD4⁺ T cells, leading to an increase in total numbers, was not the result of an increase in cellular division events, but rather due to an increase in CD4⁺ T cell survival. Using in vitro co-culture assays, it was determined that H2-M3-restricted T cells perform these functions by inducing the maturation of dendritic cells. Interestingly, H2-M3-restricted T cells were found to be more efficient at performing this function, relative to activated natural killer cells. Therefore, the adjuvant-like properties of innate-like H2-M3-restricted T cells, and possibly other MHC class Ib-restricted T cells, are targets with unique attributes that can be harnessed for future vaccine design strategies to potently focus immune responses against microbial infections.
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Edström, Måns. "Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab." Doctoral thesis, Linköpings universitet, Avdelningen för inflammationsmedicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-108910.
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Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsing-remitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4+ T cells have been shown to be of importance in disease pathology. A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS. The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4+ T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4+ T cells in vitro. We showed an imbalance in the mRNA expression of CD4+ T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated GATA3 and FOXP3 expression was decreased in RR-MS. Given the reciprocally inhibitory nature of TH subsets, this might imply not only diminished function of TH2 and TREG cells but also a permissive state of harmful TH1 and TH17 cells. The size of the peripheral TREG population was unaltered in RR-MS. When analysed in detail, activated and resting TREG were distinguished, showing clear differences in FOXP3 and CD39 expression. Furthermore, when investigating these subpopulations functionally, the ability of activated TREG to suppress proliferation of responder T cells was found to be decreased in RR-MS patients compared to controls. To further investigate this defect, the global gene expression of TREG was compared between patients and controls. Gene set enrichment analysis revealed an enrichment (over-expression) of chemokine receptor signalling genes in RR-MS TREG, possibly suggesting a role for chemokines in TREG function. A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. Furthermore, T cells from patients with MS displayed decreased responsiveness towards antigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells. The importance of CD4+ T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4+ T cell differentiation were enriched for many, not only immunerelated, diseases. Furthermore, global CD4+ T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4+ T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding. In conclusion, our results demonstrate an imbalance of peripheral CD4+ T cells in MS, along with a functional deficiency in the case of TREG. Taken together, these aberrations might result in differentiation and activation of harmful TH1 and TH17 cells, resulting in CNS tissue damage. The importance of CD4+ T cells was further demonstrated by the finding that genes associated with CD4+ T cell differentiation constitute a pleiotropic module common to a number of diseases. Investigation of natalizumab revealed drastic changes in the peripheral lymphocyte compartment caused by treatment. It also appears as treatment might influence the responsiveness of peripheral T cells to antigens. In addition, by using CD4+ T cell transcriptomics after in vitro drug exposure, prediction of treatment outcome may be possible.
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Pesce, John Thomas. "Early events leading to the host protective Th2 immune response to an intestinal nematode parasite /." Download the dissertation in PDF, 2005. http://www.lrc.usuhs.mil/dissertations/pdf/Pesce2005.pdf.
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Hartlage, Alex S. "T CELL IMMUNITY IN A SMALL ANIMAL SURROGATE OF HEPATITIS C VIRUS INFECTION." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1584101091684162.
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Istaces, Nicolas. "Transcriptional control of innate memory CD8+ T cells." Doctoral thesis, Universite Libre de Bruxelles, 2019. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/295204.
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CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled.Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished
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Iga, Natsuko. "Accumulation of exhausted CD8+ T cells in extramammary Paget’s disease." Kyoto University, 2019. http://hdl.handle.net/2433/242908.
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Wehner, Rebekka, Kristin Dietze, Michael Bachmann, and Marc Schmitz. "The Bidirectional Crosstalk between Human Dendritic Cells and Natural Killer Cells." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-137394.
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Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)-γ secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor-α and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor necrosis factor-α and IFN-γ. In conclusion, the reciprocal activating interaction between human DCs and NK cells may play a pivotal role in the immune defense against viruses and tumorsDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Okwor, Ifeoma. "Host and parasite factors that regulate secondary immunity to experimental cutaneous leishmaniasis." Frontiers publishers, 2009. http://hdl.handle.net/1993/30731.
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Leishmaniasis is a spectrum of diseases caused by several species of protozoan parasites belonging to the genus, Leishmania. The disease, which is transmitted by Sandflies, ranges from self-healing cutaneous lesions to the life-threatening visceral leishmaniasis. Cutaneous leishmaniasis, caused by L. major, is the most common form of the disease. With no vaccine available for use in humans, cutaneous leishmaniasis remains a global public health problem. Since understanding the factors that regulate effective immunity to cutaneous leishmaniasis is critical for the development of an affective vaccine and treatment strategies, the overall aim of my thesis was to decipher the host and pathogen factors that regulate immunity in cutaneous leishmaniasis.
Firstly, I show that parasite dose affects the expansion of different T cell subsets following L. major infection; with low dose infection inducing more CD8+ T cells while high dose infection induced more CD4+ T cells. However, although CD8+ T cells were important for optimal primary immunity following low dose infection, they where dispensable during secondary immunity.
Secondly, I found that blockade of LIGHT, (lymphotoxin like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes) significantly impaired DC maturation, expression of co-stimulatory molecules, and early cytokine production (IL-12 and IFN-γ) following L. major infection. Interestingly, LIGHT was completely dispensable during secondary immunity in wild type mice but was critical for effective secondary immunity in CD40 deficient mice.
Thirdly,I compared disease progression and immune response in CD40 and CD40L deficient mice infected with L. major under identical experimental conditions. I found significant differences in disease progression and immune response between CD40KO and CD40L KO mice infected with virulent L. major and treated with recombinant IL-12. My data revealed a novel pathway (CD40L-Mac-1 interaction) for IL-12 production and resistance to Leishmania major.
Collectively, this thesis provides novel insights into the mechanisms involved in the development and maintenance of protective immunity against cutaneous leishmaniasis, which could lead to the development of a more efficient and effective immunotherapeutic and/or vaccination strategies against the disease.October 2015