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1
Honey, Karen J. "Mechanisms of transplantation tolerance." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301519.
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Chung, Chen-Yen. "CD4+ T cell responses to myelin autoantigens : activation, memory and tolerance." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4013.
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Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated autoimmune disease of the central nervous system and shares many characteristics with multiple sclerosis (MS). Induction of EAE is mediated by myelin reactive CD4+ T helper (Th) cells, particularly Th1 and Th17 cells, which can be provoked by the immunization with myelin derived protein (or peptide) and Toll-like receptor (TLR) stimulus (eg, complete Freund¡s adjuvant, CFA). If given an injection of soluble peptide before immunization, mice do not develop EAE (they are tolerant). This approach has been widely applied, evoking tolerance in primary responses (i.e., in naive T cells). Therefore the first hypothesis of this thesis is that peptide induced protection from EAE is a result from T cell deletion or / and anergy. As MS patients have ongoing disease and over 85% of MS patients develop a relapsing-remitting course, memory T cells are key targets when considering peptide-induced tolerance as a therapeutic strategy. Thus, a model for ¡memory EAE¡ was established to test a second hypothesis that the myelin reactive memory T cells can be controlled by the administration of soluble peptide. Here, adoptive transfer of T cells from T cell receptor transgenic mice (2D2) recognizing myelin oligodendrocyte glycoprotein 35-55 (pMOG) was used to investigate the pMOG-reactive memory responses. Soluble pMOG administration could induce a transient expansion of 2D2 T cells followed by their loss through apoptosis. A model using double immunization was established by immunizing mice first with pMOG together with unmethylated CpG oligonucleotide (CpG) as an adjuvant, and subsequently immunizing with pMOG in CFA. This produced EAE with early onset and high incidence compared to mice which received pMOG/CFA only. Cells from mice that received the double immunization protocol produced high levels of IFN-γ, suggesting that memory T cell responses have been triggered in the mice. Administration of soluble peptide before secondary immunization could ameliorate EAE, indicating that memory T cells are susceptible to tolerance induction. pMOG-reactive memory T cells were further assessed by isolating CD4+ CD25- CD44high CD62Llow cells from pMOG-experienced 2D2 mice. These cells showed early and high production of IFN-γ, and early but transient production of IL-2, compared with naive population. These data provide basic information relevant to translating peptide-induced T cell tolerance from mice to humans.
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Erhardt, Annette. "Tolerance induction in the liver after T and NKT cell activation." kostenfrei, 2008. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2008/1032/.
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Strainic, Michael George Jr. "THE ABSENCE OF C3AR AND C5AR SIGNAL TRANSDUCTION PROMOTES T REGULATORY CELL DIFFERENTIATION AND REGULATES IMMUNOLOGIC TOLERANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1363707372.
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Seamons, Audrey. "Implications of myelin basic protein processing and presentation on T cell activation and tolerance /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/10851.
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Jangalwe, Sonal. "Regulation of Alloreactive CD8 T Cell Responses by Costimulation and Inflammation." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/907.
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CD8 T lymphocytes are a crucial component of the adaptive immune system and mediate control of infections and malignancy, but also autoimmunity and allograft rejection. Given their central role in the immune system, CD8 T cell responses are tightly regulated by costimulatory signals and cytokines. Strategies targeting signals that are critical for T cell activation have been employed in a transplantation setting to impede alloreactive T cell responses and prevent graft rejection. The goal of my thesis is to understand how costimulatory signals and inflammation regulate alloreactive CD8 T cell responses and how to target these pathways to develop more effective tools to prevent graft rejection.
Costimulation blockade is an effective approach to prolong allograft survival in murine and non-human primate models of transplantation and is an attractive alternative to immunosuppressants. I describe a novel murine anti-CD40 monoclonal antibody that prolongs skin allograft survival across major histocompatibility barriers and attenuates alloreactive CD8 T cell responses. I find that the pro-apoptotic proteins Fas and Bim function concurrently to regulate peripheral tolerance induction to allografts. Activation of the innate immune system by endogenous moIecules released during surgery or infections in transplant recipients can modulate T cell responses. However, the direct impact of inflammation on alloreactive CD8 T cell responses is not clear. Using a T cell receptor (TCR) transgenic mouse modeI, I demonstrate that inflammatory stimuli bacterial lipopolysaccharide (LPS) and the viral dsRNA mimetic poly(I:C) differentially regulate donor-reactive CD8 T cell responses by generating distinct cytokine milieus. Finally I demonstrate the role of pro-inflammatory cytokines stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in improving human B cell development in humanized NOD-scid IL2Rγnull (NSG) mice.
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Schroder, Paul. "Targeting Signal 1 of T cell Activation to Restore Self Tolerance in Type 1 Diabetes." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1381086555.
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Kaye, P. M. J. "Particle mediated co-delivery of IL-10 and antigen inhibits T cell activation but fails to induce tolerance." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302067/.
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Immune disorders such as allergy and autoimmunity are becoming increasingly common in developed countries. Self-reactive T cells exist in both healthy and autoimmune individuals. It is generally understood that hyperimmune disorders are caused by insufficient regulation, namely loss of activity of regulatory T cells. Whilst regulatory T cells exist naturally it is also possible to induce them both in vitro and in vivo. Immunotherapeutic techniques aim to provide noninflammatory exposure of antigen to the immune system with the aim of inducing antigen-specific regulatory T cells. Interleukin-10 (IL-10) is a cytokine with well known immunosuppressive qualities. It inhibits both the migration and the antigen-presenting ability of dendritic cells. It also has direct effects on T cells. Indeed, IL-10-secreting TR1 regulatory T cells were identified almost 15 years ago; their in vitro generation being dependent on exposure to IL-10. Particle-mediated DNA delivery (PMDD) is a promising method of immunisation and is especially suited to vaccines intended to have greater control over the response they induce. One of the main reasons for this is the possibility of including genes encoding immunomodulatory molecules alongside the antigen gene. This study utilises a mouse model involving the adoptive transfer of TCR-transgenic CD4+ T cells and establishes the response of these cells to PMDD immunisation. The model was then used to examine the effect of coadministration of the IL-10 gene. Its inclusion in the vaccine suppressed the response to antigen. This effect was maximal when the IL-10 gene was expressed in the same cell as the antigen gene. Using sequential immunisations the model was extended in order to study long-term effects, namely tolerance and the induction of regulatory T cells. Finally a mouse model of allergic asthma was used to examine any tolerogenic/therapeutic effects of the antigen-IL-10 vaccine. No significant longterm tolerance to antigen was identified. These results demonstrate that whilst the presence of IL-10 clearly inhibits the T cell response to antigen it does not necessarily confer tolerogenic properties on these cells. This brings into question whether IL-10 in the periphery, supplied, for example, by TR1 cells, generates fresh regulatory T cells or merely inhibits the response to a particular antigenic challenge.
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Horne, Phillip Howard. "Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1188397900.
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Serr, Isabelle Daniela Verfasser], Anette-Gabriele [Akademischer Betreuer] Ziegler, de Angelis Martin [Gutachter] [Hrabé, Ludger [Gutachter] Klein, and Anette-Gabriele [Gutachter] Ziegler. "T cell activation versus tolerance induction in islet autoimmunity / Isabelle Daniela Serr ; Gutachter: Martin Hrabé de Angelis, Ludger Klein, Anette-Gabriele Ziegler ; Betreuer: Anette-Gabriele Ziegler." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1168380286/34.
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Serr, Isabelle Daniela Verfasser], Anette-Gabriele [Akademischer Betreuer] [Ziegler, de Angelis Martin [Gutachter] Hrabé, Ludger [Gutachter] Klein, and Anette-Gabriele [Gutachter] Ziegler. "T cell activation versus tolerance induction in islet autoimmunity / Isabelle Daniela Serr ; Gutachter: Martin Hrabé de Angelis, Ludger Klein, Anette-Gabriele Ziegler ; Betreuer: Anette-Gabriele Ziegler." München : Universitätsbibliothek der TU München, 2018. http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20180917-1366247-1-2.
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Rivera, Cifuentes Claudia Andrea. "Intraepithelial dendritic cells : origin and function." Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5167.
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Les cellules dendritiques (CDs) patrouillent les tissus et transportent les antigènes vers les ganglions lymphatiques pour initier des réponses immunitaires adaptatives. Au sein des tissus, les CDs constituent une population cellulaire complexe composée de sous-types distincts pouvant présenter différents états d'activation et fonctions. La façon dont les signaux tissulaires orchestrent la diversification des CDs reste insaisissable. La Lamina Propria (LP) de l'intestin grêle (IG) est enrichie par une population particulière de cCD2 exprimant les intégrines CD103 et CD11b. Une fraction de ces cellules peut transmigrer dans l'épithélium à l'état d'équilibre et en proportion plus élevée lors d'une infection. Cependant, les conséquences d'un tel événement sur l'identité et le destin de ces cellules sont inconnues. En utilisant l'analyse de séquençage d'ARN unicellulaire, nous avons constaté que la transmigration des CDs CD103+CD11b+ dans l'épithélium modifie profondément leur profil transcriptomique caractérisé par une baisse d'expression des gènes inflammatoires et une augmentation d'expression des gènes associés à l'activité antimicrobienne. Nous avons ensuite décrit que l'intestin grêle comprend deux pools de cCD2s provenant de précurseurs de préCDs communs : (1) cCD2s CD103+CD11b+ de la LP qui sont des cellules pro-inflammatoires de type mature et (2) des cCD2s intraépithéliales qui présentent un phénotype similaire à celui des CDs immatures induisant des propriétés tolérogènes des lymphocytes T. Ce phénotype résulte de l'action de l'acide rétinoïque d'origine alimentaire (ATRA), qui améliore la contractilité de l'actomyosine et favorise la transmigration des cCD2s de la LP vers l'épithélium. Les cCD2s sont alors influencées par des indices environnementaux spécifiques à l'épithélium comprenant l'ATRA lui-même ainsi que le composant muqueux Muc2. Par conséquent, en atteignant des niches sous-tissulaires distinctes, les CDs peuvent exister sous forme de cellules immatures et matures dans le même tissu, révélant un nouveau mécanisme de diversification fonctionnelle des CDsDendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population made of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Particularly, the small intestine (SI) Lamina Propria (LP) is enriched in a peculiar population of cDC2s expressing the integrins CD103 and CD11b. Interestingly, a fraction of these cells can transmigrate into the epithelial layer both at steady state and in higher proportion upon infection. However, the consequences of such event on the identity and fate of these cells is unknown. By using single cell RNAseq analysis, we found that their epithelial colonization deeply modifies their transcriptomic profile, downregulating inflammatory genes expression and stimulating the transcription of antimicrobial genes. We then further described that the small intestine includes two pools of cDC2s originating from common preDC precursors: (1) lamina propria CD103+CD11b+ cDC2s that are mature-like pro-inflammatory cells and (2) intraepithelial cDC2s that exhibit an immature-like phenotype and induce tolerogenic T lymphocyte properties. Intraepithelial cDC2 phenotype results from the action of food-derived retinoic acid (ATRA), which enhances actomyosin contractility and promotes LP cDC2 transmigration into the epithelium. There, cDC2s are imprinted by environmental cues including ATRA itself and the mucus component Muc2. Hence, by reaching distinct sub-tissular niches, DCs can exist as immature and mature cells within the same tissue, revealing a novel mechanism of DC functional diversification
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Brown, David Spaulding. "CD4+ T Cell Responses: A Complex Network of Activating and Tolerizing Signals as Revealed by Gene Expression Analysis: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/230.
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Immunologic self-tolerance is maintained by both central and peripheral mechanisms. Furthermore, regulation of mature lymphocyte responses is governed by inhibitory as well as stimulatory signals. TCR recognition of cognate peptide bound to MHC molecules provides the initial stimulus leading to T lymphocyte activation and determines the antigen specificity of any subsequent response. However, lymphocytes must discriminate between foreign and self antigens presented by self-MHC molecules to maintain self tolerance and avoid pathological autoimmunity. Consequently, TCR ligation alone is reported to result in abortive activation, T cell anergy, apoptosis, and tolerance. Under normal physiological conditions, costimulatory signals modify lymphocyte responsiveness to TCR ligation to prevent autoimmunity while enabling robust responses to foreign antigen. Members of the CD28/B7 superfamily provide the critical secondary signals essential for normal immune cell function.
CD28 is an essential positive costimulatory molecule with critical functions in thymic development, lineage commitment, and regulation of peripheral lymphocyte responses to antigenic stimuli. CD28 ligation by APC-expressed B7 molecules alters proximal signaling events subsequent to MHC/TCR interactions, and initiates unique signaling pathways that alter mRNA stability and gene transcription. Furthermore, CD28 signaling is required for regulatory T cell development and function. Thus, CD28 has a central role in both potentiating lymphocyte activation mediated by TCR engagement and regulating peripheral tolerance. In contrast, Ctla-4 mediates an inhibitory signal upon binding B7 molecules on an antigen-presenting cell. Its importance in governing lymphocyte responses is manifested in the fatal lymphoproliferative disorder seen in Ctla-4-/- mice. The lymphocyte proliferation is polyclonal, antigen and CD28 dependent, and arises from defects in peripheral CD4+T cell regulation. The high percentage of peripheral T lymphocytes expressing activation markers is accompanied by lymphocyte infiltration into numerous non-lymphoid tissues and results in death by 3-4 weeks. While still controversial, Ctla-4 signaling has been reported to be essential for induction of peripheral T lymphocyte tolerance in vivo and in some model systems is proposed to regulate both T lymphocyte anergy induction and the immune suppressive effects of some regulatory T cells in the prevention of autoimmunity.
Signaling pathways activated by TCR ligation and CD28 costimulation have been extensively characterized. In contrast, the mechanisms mediating Ctla-4 maintenance of tolerance remain largely unknown. Ctla-4 gene expression is tightly controlled during T cell development and activation, and its intracellular localization and expression on the cell surface is regulated by numerous pathways and intermediates. While a tailless Ctla-4 mutant is capable of inhibiting T cell activation, recent studies have shown that a ligand independent form of Ctla-4 is also capable of providing an inhibitory signal to T lymphocytes. In conjunction with the strictly controlled expression kinetics and the perfect amino acid homology between the intracellular domains of mouse and human Ctla-4, this data suggests that Ctla-4 may participate in the modulation or initiation of intracellular signaling pathways.
Positive and negative costimulatory receptors on the T cell modify lymphocyte responses by altering both quantitative and qualitative aspects of the lymphocyte response including threshold of activation, cytokine secretion, and memory responses. Positive costimulation augments T cell responses, in part, by downregulating the expression of genes that actively maintain the quiescent phenotype. This study was initiated to determine the role of Ctla-4 ligation in modifying the global gene expression profile of stimulated T cells and to determine if the Ctla-4 mediated maintenance of T cell tolerance was achieved, in part, by altering the transcription of quiescence genes necessary for the prevention of T cell activation subsequent to TCR and CD28 stimulation.
Previous studies investigating the influence of Ctla-4 ligation on transcriptional profiles of activated lymphocytes detected only quantitative alterations in the transcriptional regulation initiated by CD28 signaling. In contrast, our data suggests that quantitative effects of Ctla-4 ligation that differentially influence pathways acting downstream of stimulatory receptors results in a stable and qualitatively unique phenotype detectable at the level of the transcriptome. Thus, the cumulative effect of Ctla-4 signaling is unique and not constrained to reversing alterations in expression initiated by CD28. In addition, Ctla-4 ligation can be shown to influence T lymphocyte responsiveness and the resulting global expression profile within 4 hours after stimulation and prior to detectable Ctla-4 surface expression. In a subpopulation of T cells, TCR stimulation activates pathways that result in commitment to activation with 2-6 hours. In contrast, CD28 signaling must be maintained for 12-16 hours to ensure maximal responses at the population level. The period of sensitivity to Ctla-4 inhibition of activation is more constrained and does not extend beyond 12 hours. Together, these data support a potential role for Ctla-4 in modification of the early transcriptional response and may explain various alterations in phenotype resulting from Ctla-4 ligation that have been reported in secondary responses.
Identification of genes involved in lymphocyte activation, maintenance of selftolerance, and attenuation of immune responses opens the door to therapeutic manipulation of the pathways implicated. CD28 costimulation results in general amplification of TCR-initiated transcriptional responses, and specifically alters the expression profile of a subset of genes. In contrast, Ctla-4 ligation directly and specifically alters the expression of a select group of genes when ligated, and results in minimal suppression of the global CD28-mediated costimulatory transcriptional response. Ctla-4 regulated genes comprise a heterogeneous family, but include known quiescence factors, transcriptional regulators, and various determinants of cell cycle progression and senescence. The role of Ctla-4 in maintaining self-tolerance indicates that targeted manipulation of these gene products presents a novel therapeutic opportunity, and suggests that the mechanisms involved in Ctla-4-mediated maintenance of peripheral T cell tolerance and regulation of immune responsiveness is more nuanced than previously thought. In addition, this study provides the most comprehensive description of global gene expression during primary lymphocyte activation yet available. The integration of statistical and bioinfomatics analyses with large scale data mining tools identifies genes not previously characterized in lymphocytes and can direct future work by predicting potentially interacting gene products and pathways.
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Letscher, Hélène. "Étude des propriétés régulatrices d’une population de précurseurs de cellules dendritiques plasmacytoïdes conditionnée par le CpG dans le cadre de réponses auto-immune et allogénique Innate activation primes bone marrow plasmacytoid dendritic cell precursors for tolerance Rôle protecteur des CpG-pre-pDC dans le cadre d’une réponse allogénique : la maladie du greffon contre l’hôte." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2171&f=13417.
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Les progéniteurs hématopoïétiques présentent la faculté de détecter des signaux infectieux et inflammatoires. Leur éducation précoce par de tels signaux au sein de la moelle osseuse avant leur sortie vers la périphérie peut influencer l'évolution des réponses immunes. Alors que les cellules dendritiques plasmacytoïdes matures peuvent soit aggraver soit améliorer des maladies auto-immunes ou allogéniques, nous avons exploré la possibilité que de tels signaux innés confèrent des propriétés immunorégulatrices à des précurseurs médullaires des pDC. Nous avons caractérisé une population médullaire émergeant après interaction avec un agoniste du Toll-like receptor-9, l'oligonucléotide CpG, qui présente le phénotype c-kit+Sca-1+B220intPDCA-1+, est engagée dans la voie des cellules dendritiques plasmacytoïdes (pDC) et l'avons dénommée CpG-pre-pDC. Nous avons évalué le potentiel immunorégulateur des CpG-prepDCs en opérant leur transfert adoptif dans deux types de pathologies murines : l'Encéphalite Auto-immune Expérimentales (EAE), un modèle de sclérose en plaques qui est une maladie auto-immune, ainsi que la maladie du greffon contre l'hôte (GVHD) qui est une réponse allogénique. Il s'est avéré que le transfert d'un nombre assez faible de précurseurs (80 000 en EAE et 200 000 en GVHD) est capable de limiter la maladie à différents temps cliniques. De façon intéressante, les CpG-pre-pDC migrent spécifiquement à la moelle épinière dans l'EAE et à la rate dans la GVHD où leur descendance conserve un phénotype de pDC encore relativement immature. Dans le cadre de l'EAE, la descendance des précurseurs injectés produit essentiellement de l'IL-27 et du TGFß et plus modestement du GM-CSF. Au niveau du système nerveux central inflammé, elles font dévier la réponse immunitaire des lymphocytes T CD4+ infiltrants d'un profil pro-inflammatoire (IFNy+ GM-CSF+ IL-17+) vers un profil anti-inflammatoire (TGFß+, IL-27+, IL-17-, GM-CSFlo). L'utilisation de précurseurs déficients dans chacune de ces deux cytokines a permis de démontrer que TGFß et IL-27 interviennent séquentiellement dans la protection conférée par les CpG-prepDCs, le TGFß à des temps précoces et l'IL-27 aux phases tardives de la maladie. Des mécanismes semblables interviennent dans la protection envers la GVHD conférée par les CpG-prepDCs, car leur descendance est toujours capable de produire du TGFß mais cette fois en association avec l'IL-12, une autre cytokine de la même famille que l'IL-27. Par ailleurs, ces cellules sont capables de diminuer la production d'IL-17 tant par les lymphocytes T CD4+ que par les CD8+. Une thérapie cellulaire avec l'équivalent humain des CpG-pre-pDCs pourrait constituer un nouvel outil thérapeutique pour le traitement à la fois de la sclérose en plaques réfractaire et de la maladie du greffon contre l'hôte soit injectés seuls soit en enrichissement des greffes de cellules souches hématopoïétiques qui sont pratiquées dans ces deux maladiesHematopoietic progenitors can sense innate signals. Their early education by such signals within the bone marrow, prior to their egress, may have considerable impact on the outcome of immune responses. While mature plasmacytoid dendritic cells (pDC) are known to either aggravate or ameliorate disease both auto-immune and allogeneic, it remains unknown whether immune regulatory function can be stably imprinted at the precursor stage in the pDC lineage onwards. We herein investigated whether activation with the oligonucleotide CpG, a Toll-like receptor-9 agonist, confers to bone marrow pDC precursors (CpG-prepDCs) characterized by the c-kit+Sca-1+B220intPDCA-1+ phenotype the capacity to protect against two kinds of murine immune pathologies: Experimental Autoimmune Encephalomyelitis (EAE), a model of multiple sclerosis which is an autoimmune disease and graft versus host disease (GVHD), an allogeneic response. We demonstrate that the adoptive transfer of relatively low number of CpG-pre-pDCs (80.000 in EAE and 200.000 in GVHD) was able to clinically reduce both diseases. Interestingly, CpG-pre-pDCs migrated to the spinal cord in EAE and to the spleen in GVHD where their progeny retained a relatively immature pDC phenotype. In EAE, the progeny of CpG-pre-pDCs massively produces IL-27 and TGFß and moderately GM-CSF. In the inflamed central nervous system, the progeny switches the immune response of infiltrating CD4+ T cells from pro-inflammatory (IFNy+ GM-CSF+ IL-17+) to anti-inflammatory (TGFß+, IL-27+, IL-17-, GM-CSFlo). The key role of TGFß and IL-27 was assessed using precursors incapacitated for the production of each of those cytokines. These experiments demonstrated that the two soluble factors acted sequentially: TGFß ensures early phases of the immunomodulation mediated by the CpG-pre-pDC while IL-27 is required for later protection. In GVHD, the mechanisms of protection are different yet similar in some ways. As for EAE, the progeny of CpG-pre-pDCs is still able to produce TGFß but this time in combination with IL-12, another cytokine from the IL-27 family. Additionally, those cells were able to reduce the IL-17 production by both pathogenic CD4+ and CD8+ T cells. The human equivalent of CpG-pre-pDC could be a new therapeutic tool in patients with multiple sclerosis or graft versus host disease either per se or enriched in the hematopoietic stem cell transfer already implemented to treat those two immune conditions
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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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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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Phillips, Roderick J. "Biochemical mechanisms underlying T-cell activation." Thesis, Brunel University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291527.
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Tilney-Bassett, Amanda L. "Phospholipid metabolism in T-cell activation." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239331.
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Lever, Melissa. "Phenotypic models of T cell activation." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:83a14d45-484b-4d20-a31f-74063f49adce.
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T cells are important immune cells that initiate and regulate immune responses to cell surface antigens. The productive binding of T cell receptors (TCRs) to cell surface antigens initiates a signal transduction cascade within the T cell that results in T cell effector functions. It is established that the dose of antigen and the binding parameters between TCRs and antigen determines the functional response of the T cell. Although much progress has been made to identify the molecules that constitute the intracellular signalling network, it remains unclear how these molecules interact with each other to convert antigen concentration and binding paramters into a downstream response. A mathematical model of T cell activation can provide insight into this network, however despite extensive study, there is still no conclusive model. We have taken a phenotypic modelling approach to study T cell signalling. We begin by reformulating the existing models of T cell activation in the literature under a consistent framework so that they can be categorised. This analysis reveals that detailed, quantitative studies of T cell activation are required to test the models. We address this by using a high affinity T cell receptor system to generate dose-response data. The antigens have a 105 range in affinity for the TCR and are presented over a very wide range of concentrations. The dose-response assays show that there is an optimal affinity at low antigen dose, and the dose-response profiles can be seen to decrease at high antigen doses. We then generate simple a model that can exhibit these phenotypes, which we term the kinetic proofreading with limited signalling coupled to an incoherent feed forward motif model. The structure of this model has implications for the structure of the T cell signalling network. The model indicates that there is a mechanism that causes activated TCRs to become inert on a timescale of around ten minutes, which we attribute to their internalisation and down-modulation. The incoherent feed forward motif suggests two parallel inhibitory and activatory pathways within the T cell that both act on a downstream molecule. Further research must be done to identify the molecules involved in this motif.
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Lute, Kenneth D. "Costimulation and tolerance in T cell immunotherapy." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141850521.
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Gorak-Stolinska, Patricia. "Activation induced cell death in human T cell subsets." Thesis, King's College London (University of London), 2002. http://kclpure.kcl.ac.uk/portal/en/theses/activation-induced-cell-death-in-human-t-cell-subsets(eb708e24-eccb-42fc-8930-d62ddf6794c1).html.
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Jansson, Andreas Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Modelling T helper cell activation and development." Awarded by:University of New South Wales. School of Biotechnology and Biomolecular Sciences, 2006. http://handle.unsw.edu.au/1959.4/30602.
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T helper (Th) cell activation and development is one of the most critical events in regulating the adaptive immune response. Understanding its regulation could be of great therapeutical value as many severe diseases are associated with failure in controlling T cell activation and development. However, the regulation of T cell activation appears to be one of the most complex set of cellular and molecular interactions known in the immune system. There is therefore an urgent need for tools to unravel this complexity, and to make use of the quantitative experimental data. To address this issue, mathematical and computational models, based on rigorous biophysical and kinetic data, were developed to study the specific role of some of the major costimulatory molecules involved in Th cell activation, and others developed to investigate proposed theories about mechanisms involved in Th cell differentiation. The simulations of costimulation reveal new implications for the function of the costimulatory molecules CD28 and CTLA-4, and their ligands B7-1 and B7-2, and show how binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects, all profoundly influence complex formation at the immunological synapse. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be, as has been previously proposed, due to the different binding properties of B7-1 and B7-2. Simulations of Th cell development reveal that both instructive and selective processes are likely to be involved in Th cell differentiation. In addition, further simulations indicate that Th2 cells are more likely to become dominant by inhibiting Th1 cells (negative selection), rather than selecting their own growth (positive selection). This thesis also includes an experimental work in which the immunomodulatory role of the bacterial signalling molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) was analysed. This study strongly suggests that OdDHL suppresses Th cell activation and development, and that it is likely targeting the intracellular signalling events involved in the early stages of Th cell activation.
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Marcello, Jonas [Verfasser], Rudolf [Akademischer Betreuer] Grosschedl, and Alexander [Akademischer Betreuer] Tarakhovsky. "PRC2 during T cell development and activation." Freiburg : Universität, 2017. http://d-nb.info/1154681823/34.
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Lawton, R. L. "Cytotoxic T cell activation in the mouse." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278527.
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Zheng, Huan Ph D. Massachusetts Institute of Technology. "Multi-scale models of T cell activation." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/62065.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
The overarching theme of this thesis is to develop and apply multi-scale computational techniques adopted from physical sciences to study a key phenomenon underlying the adaptive immune response: the activation of T cells. The specific objectives are: 1) develop efficient and versatile computational frameworks to study multi-scale biological systems in silico; 2) obtain mechanistic insights into how T cells are triggered in vivo. The first problem investigated in this thesis addressed a controversy regarding when and how T cells alter migratory patterns in lymphoid tissues, as observed in intravital microscopy experiments. By developing a lattice-based model for T cell migration coupled with a mechanistically motivated simple scheme for T cell activation, I showed that the quantity and quality of cognate antigen (Ag) presented by dendritic cells (DC) dictate such changes. The results from theoretical and computational analyses were not only in agreement with synergistic experiments, but also made predictions that have been tested positively. Furthermore, I identified a consolidated measure of Ag quantity and quality, which provides a unifying conceptual framework for considering diverse future experimental results. The results from this study also suggested that T cells may integrate sub-optimal signals derived from successive encounters with DCs to achieve full activation. However, an underlying molecular mechanism that may confer such "short term memory" of exposure to Ag is not known. I explored the possibility that the hysteresis resulting from positive feedback regulation of the catalytic conversion of a G-protein RasGDP to RasGTP in the T cell receptor (TCR) membrane-proximal signaling network may enable such "short term memory". I developed a multiscale computational model that combines stochastic simulations of the TCR membrane-proximal signaling network with T cell migration. The results showed that this hysteresis can enable T cells to integrate signals derived from weakly stimulatory DCs and may greatly enhance the detection sensitivity during disease onset when Ag presentation is low. The computational framework developed in this study can be readily adapted to examine diverse biological systems where signaling and cell motion need to be studied simultaneously. For example, the model was modified to investigate a DC-mediated mechanism for signal integration, and our results suggest that this mechanism is less likely. Initial steps were also taken to construct a macroscopic model that aims to study how T cell activation impacts observations at the organismic level. Preliminary results for how microscopic receptor-ligand interactions affect the proliferation of different T cell types are presented. Directions for future research are suggested based on these findings.
by Huan Zheng.
Ph.D.
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Wong, Ryan. "Breaking T-cell tolerance in chronic lymphocytic leukaemia." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/45673/.
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CLL is an incurable B-cell malignancy associated with profound tumour cell-mediated immune dysfunction. It therefore represents a challenging disease for the successful application of immunotherapeutic strategies aimed at promoting anti-tumour T-cell responses. In this study, extensive immunophenotypic analysis of T-cells from the blood of CLL patients was performed, in order to better characterise their dysfunctional status within the disease. Analysis of CLL patient blood samples revealed a skewing of T-cells towards a highly differentiated effector memory phenotype as well as the expression of markers associated with exhaustion/senescence (CD28- and CD57+) and immunosuppressive molecules (PD-1 and CD200). In addition this study revealed the expansion of CD8+ T-cells in a subset of CLL patients leading to an inversion in the normal CD4:CD8 ratio. The presence of an inverted CD4:CD8 ratio was subsequently shown to be associated with a shorter time to first treatment and reduced progression-free survival. Characterisation of T-cells identified several molecules that could be targeted therapeutically in order to break T-cell tolerance in CLL patients and potentially restore normal immune responses. Investigation of the immunosuppressive molecules PD-1 and CD200 showed that they are over expressed in CLL patients, suggesting that they may be involved in maintaining T-cell tolerance in the disease. However, blockade of PD-1-PDL-1 and CD200-CD200R signalling pathways failed to enhance T-cell responses from CLL patients in vitro. Investigation of an alternative approach to enhance T-cell responses in CLL involved the use of a bi-specific antibody targeting CD19 and CD3 called blinatumomab. In vitro testing showed that blinatumomab can induce T-cell activation, promoting the release of pro-inflammatory cytokines and granzyme B secretion from both CD4+ and CD8+ T-cells. In addition, blinatumomab was shown to mediate T-cell dependent killing of CLL cells requiring the formation of T-cell:CLL cell conjugates. Finally this study provided clear evidence that blinatumomab can break T-cell tolerance in CLL and strongly advocates the progression of blinatumomab into clinical trials as a novel therapeutic agent in CLL.
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Thompson, Angus Gordon. "Dendritic cell NFkB function in T cell activation and autoimmunity /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18273.pdf.
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Brodie, Douglas William. "Molecular analysis of T cell costimulatory pathways." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249517.
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Bonnard, Madeleine. "Novel roles for CD4 in T cell activation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0006/NQ41108.pdf.
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Moldovan, Maria-Cristina. "Role of CD4 dimerization in T cell activation." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82936.
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Key to development of immunotherapies and vaccines is a thorough understanding of the complex pathways that govern T cell activation. On helper T lymphocytes, the CD4 molecule is a critical player in the early stages of activation, serving to enhance recognition of MHC-peptide complexes by the TcR and to facilitate efficient p56lck recruitment in the vicinity of the engaged TcR:CD3 signalling module. Originally, the CD4 molecule was believed to exist as a monomer on the cell surface; however, within the last years, a growing body of crystallographic, computer modeling and functional studies has suggested that CD4 might assume a dimeric/oligomeric state.Here, we provide direct experimental evidence for the existence of CD4 dimers on the surface of transfected cells from haematopoietic and fibroblastic origin, as well as in primary T lymphocytes. Furthermore, we accurately map the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. Specifically, we show that CD4 dimerization is required for efficient IL-2 production, yet appears without effect on early TcR-associated signalling. Using FRET video microscopy to visualize the dynamics of CD4 molecules during T cell activation, we reveal that CD4 dimers only promote immunological synapse formation, then further accumulate within the synapse.
Overall, the study presented in this thesis sheds light on the refined molecular interplay of the various surface receptors and signalling modules that dictates the efficiency of the T lymphocyte antigenic response.
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Sporri, Roman Andreas. "Reciprocal control of T cell and APC activation." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411991.
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Morgan, Sara Hannah. "Molecular aspects of antibody mediated T cell activation." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:8c30ca07-b93b-46a7-aa86-01f94ee97e97.
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The normal physiological activation of naive T cells requires the engagement of both the T cell receptor (TCR) and the co-stimulatory molecule, CD28. However, a group of monoclonal antibodies (mAbs) have been identified that are able to activate T cells in vitro and in vivo via CD28 engagement alone. Two defining characteristics found in all CD28 superagonist mAbs are their membrane proximal CD28 epitopes and the requirement for mAb immobilisation. To investigate whether agonistic mAbs to similar cell molecules could be identified based on epitope position alone, mAbs to the inhibitory receptor PD-1 were generated and characterised. Using a drastic mutation-based epitope mapping technique, one mAb was identified with a membrane proximal epitope along with two other mAbs with membrane distal epitopes. These mAbs were tested for triggering activity in a hybridoma stimulation assay. mAb stimulation was observed with all three mAbs but only in cells expressing a PD-1 chimera that associated with the TCR and the strength of activation was dependent on epitope location. Cross-linking of a monomeric PD-1/CD28 chimera with a pair of anti-PD-1 mAbs resulted in signalling in this system, however, suggesting a role for ligand aggregation in addition to epitope position in mAb signalling. To further investigate the role of epitope position in CD28 superagonism, a cell line expressing a chimeric form of CD28 was created wherein the superagonistic mAb epitope was moved to a membrane distal position. When stimulated with a CD28 superagonist mAb signalling was no longer observed. However stimulation with another mAb that had an epitope to a membrane proximal location on the chimera resulted in superagonistic effect. These results show that epitope location is the dominant cause of T cell stimulation observed by CD28 superagonist mAbs and that epitope dependent mAb signalling is possible in other T cell surface molecules. The work described in this thesis has implications for both the development of immune modulating mAb therapeutics and for the general mechanism of triggering of cell surface receptors dependent on extrinsic tyrosine kinases.
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Friedman, Rachel Sharon. "Early T cell activation in the lymphoid milieu." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3251945.
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Thesis (Ph.D.)--University of California, San Francisco, 2007.Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0876. Adviser: Matthew F. Krummel. Includes supplementary digital materials.
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Carr, Erikka. "Regulation of glutamine utilization during T cell activation." College Park, Md.: University of Maryland, 2007. http://hdl.handle.net/1903/7395.
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Thesis (M.S.) -- University of Maryland, College Park, 2007.Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Wilson, Anne. "The role of CD28 in T cell activation." Thesis, University of Bath, 1997. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362221.
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Blish, Catherine Anne. "Modulation of T cell function and T cell receptor repertoire during the induction of peripheral tolerance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8323.
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Pothion, Hugo. "Contribution au développement de stratégies thérapeutiques pour la réparation fonctionnelle de processus neurodégénératifs : apport du peptide PSELT dérivé de la sélénoprotéine T et de cellules souches. Therapeutic benefit of the SELENOT mimetic PSELT in facial nerve regeneration AMPK activation of PGC-1alpha/NRF-1-Dependent SELENOT gene transcription promotes PACAP-induced neuroendocrine cell differentiation through tolerance to oxidative stress Selenoprotein T : an essential oxidoreductase serving as a guardian of endoplasmic reticulum homeostasis." Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR030.
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Le système nerveux périphérique a des capacités intrinsèques de régénération, mais la récupération motrice est insuffisante dans les cas de lésions les plus graves. Si la chirurgie reste l'approche thérapeutique "de référence", son efficacité est souvent limitée et diverses stratégies alternatives ont été développées, comme la thérapie à base de cellules souches. Cependant, on observe également une régénération incomplète des nerfs, et plusieurs approches visent à améliorer le potentiel de ces cellules. Parmi celles-ci, la modulation de l'environnement redox à l'aide de molécules antioxydantes est l'une des plus prometteuses. La sélénoprotéine T (SELENOT) est une oxydoréductase qui fait partie de la famille des sélénoprotéines, l'une des plus importantes familles d'enzymes antioxydantes dans l'organisme. Récemment, un peptide mimétique (PSELT) dérivé de SELENOT a montré un effet cardioprotecteur et neuroprotecteur dans un environnement nocif. La première partie de cette étude visait à évaluer le potentiel thérapeutique du PSELT dans un modèle de lésion du nerf facial chez le rat. Puis, nous avons recherché si le PSELT pouvait potentialiser l’effet thérapeutique d’une thérapie basée sur les cellules souches dérivées des capsules frontières (CF), une population de cellules souches située dans le derme qui a montré un fort potentiel neurogènique. Immédiatement et 48 heures après l'opération, le PSELT a été injecté dans une chambre de régénération d’origine veineuse dont le rôle était de réunir les deux rameaux d’un nerf facial axotomisé au niveau de la sortie du foramen stylo-mastoïdien. L’évaluation motrice des vibrisses, réalisée trois mois après la lésion, a montré que PSELT améliorait la récupération motrice de manière plus efficace comparée aux animaux témoins et à ceux ayant reçu un traitement chirurgical standard. Ces bénéfices cliniques ont été confirmés par des analyses électromyographiques et histologiques qui ont révélé une meilleure repousse nerveuse, une meilleure myélinisation et une réinnervation plus fine des muscles cibles. La combinaison de PSELT avec des cellules souches dérivées des CF n'a pas potentialisé la régénération nerveuse par rapport à la thérapie basée sur le PSELT seul, tant au niveau clinique qu'histologique. Dans l'ensemble, nos résultats indiquent que le PSELT offre un avantage thérapeutique pour traiter les lésions des nerfs périphériques par rapport aux approches de chirurgie et de thérapie cellulaire, et constitue donc un candidat précieux pour la médecine régénérativePeripheral nervous system has intrinsic regeneration abilities, but motor recovery is insufficient in the most severe cases of lesions. Although surgery remains the “gold standard” therapeutic approach, its efficiency is often limited, and various alternate strategies have been developed such as stem cell-based therapy. However, uncomplete nerve regeneration is also observed, and several approaches aim to improve the potential of these cells. Among them, redox environment modulation using antioxidant molecules is one of the most promising. Selenoprotein T (SELENOT) is an oxidoreductase which is a member of the selenoprotein family, one of the most important family of antioxidant enzymes in the organism. Recently, a mimetic peptide (PSELT) derived from SELENOT has shown a cardioprotective and a neuroprotective effect in a noxious environment. The first part of this study aimed at evaluating the therapeutic potential of PSELT in a facial nerve injury model in rat. In a second part, we asked whether PSELT could improve a stem cells-based therapy using boundary cap (BC) stem cells, a stem cell population located in the dermis which showed a high neurogenic potential. Immediately and 48 hours after the surgery, PSELT was injected into a free femoral vein interposition graft bridging the stumps of an axotomized facial nerve at the level of the exit point of the stylomastoid foramen. Three months later, motor performance of the vibrissae has been analyzed. PSELT significantly improved motor recovery compared to control, and end suture-treated animals. These results were confirmed by electrophysiological and histological analysis which highlighted a better nerve regeneration, an increased myelination and a more specific innervation of the whisker pad in the PSELT-treated group. Combination of PSELT with BC-derived stem cells did not improve further nerve regeneration compared to the PSELT-based therapy alone, both at the clinical and histological levels. Altogether, our results indicate that PSELT offers a therapeutic advantage to treat peripheral nerve lesion compared to surgery and cell therapy approaches, and thus constitutes a valuable candidate for regenerative medicine
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Hochweller, Kristin. "The roles of CD40 and OX40 during the induction of T cell tolerance versus T cell immunity." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/14081.
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Tolerance induction is thought to be the result of peptide presentation by resting DC, which are lacking full costimulatory potential. The precise signals that drive a T cell towards tolerance, rather than a productive immune response, are not well defined. This project has addressed this issue by asking three questions: A. Can exogenous ligation of defined costimulatory receptors convert a tolerogenic signal into an immunogenic one? B. How does expression of the costimulatory pairs CD40-CD154, OX40L-OX40, and RANK-RANKL on DC or T cells respectively differ during induction of T cell tolerance versus immunity? C. Can we mimic tolerance induction by giving antigen-loaded DC lacking CD40? It was found that agonistic antibodies to CD40 and OX40 converted a tolerance signal to an immunogenic one, preventing the induction of tolerance. CD154, OX40 and RANKL are expressed on T cells under conditions leading to either tolerance or immunity. Up-regulation/induction of CD40, OX40L and RANK on DC, however, was only observed during the induction of T cell immunity. The administration of antigen-loaded CD40-deficient DC mimicked tolerance induced by soluble peptide. Collectively, the results suggest that the CD40-CD154 interaction provides an important checkpoint in the decision between T cell tolerance and immunity. Investigating the process of tolerance induction may provide a rational basis for therapeutic targeting of costimulatory pairs in adverse immune reactions in humans.
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Holderness, Jeffery Scott. "Select Procyanidins induce gammadelta T cell activation and proliferation." Thesis, Montana State University, 2008. http://etd.lib.montana.edu/etd/2008/holderness/HoldernessJ0508.pdf.
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Many pharmaceutical drugs in use today were originally identified in plants from traditional medicine. However, there remain many plants in traditional medicine that produce confusing immune responses and are therefore unlikely candidates for pharmaceutical drugs. The effects of some of the traditional medicines that induce these confusing immune responses may now be explained by recent advances in the characterization of our immune system, namely in our understanding of the unique functions of the γδ T cell. These γδ T cell functions include tissue repair and homeostasis, cancer infiltration and clearance, pathogen detection and cytokine response, and antigen presentation. Although there are currently therapies being studied to increase the effector function of γδ T cells, these techniques are only active on a limited population of γδ T cells, the human Vδ2 subset. Although these cells are potent effectors against pathogens and some cancers, Vδ2 T cells demonstrate a restricted tissue distribution and limited effector function in other γδ T cell host defense responses. As such, we screened compound libraries and traditional medicines for agonists with activity encompassing alternative γδ T cell subsets. Tannins derived from select plant species are able to fulfill this role as demonstrated by the activation and expansion of γδ T cell subsets not responsive to current γδ T cell expansion therapies. The ability of tannins to expand these γδ T cell populations will potentially increase the therapeutic range of γδ T cells and may be used as treatments for wound healing as well as in the clearance of solid tumor cancers.
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Poudrier, Johanne. "Contact events in T help for B cell activation." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28517.
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The generation of an Ab response is modulated by contact and cytokine mediated T help for B cells. Here we show that murine splenic small resting B cells do not express mRNA for, or bear IL-2R. Accordingly, these cells do not respond to IL-2. T- contact events induce IL-2R expression on B cells and this is inhibited by blocking of CD40, MHC II or CD54. Although CD40 ligation on its own induces B cell proliferation, it does not confer IL-2 responsiveness. In contrast, signalling through MHC II and CD54 synergizes with IL-5 to induce functional IL-2R on B cells. Moreover, physiological, gp39$ rm sp{low},$ T help for B cell IL-2 responsiveness is equivalently dependent on ligation of CD40, CD54 and MHC II, and requires prior sIg signalling. IL-5 synergizes with either LPS or Th to render B cell responses to IL-2 autonomous of further stimulus. Thus, expression of a functional IL-2R is a marker of B cell activation which appears to be tightly regulated through sIg signals and T-contact events and can be modulated by cytokines.
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Zech, Tobias Nikolai. "Lipid protein interactions at sites of T cell activation." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531794.
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Lind, Liza. "Non-coding RNA in T cell activation and function." Thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-96966.
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For a long time research has focused on the protein-coding mRNA, but there is a complex world of non-coding RNAs regulating the human body that we yet know very little about. Non-coding RNAs (ncRNAs) are involved in modulation of different cell processes including proliferation, differentiation and apoptosis. In the current study the role of ncRNAs in T cell activation and function was investigated. T cells are important mediators of immune responses, for example upon viral infections. The T helper cells (TH or CD4+ cells) are involved in orchestrating immune processes like aiding the activation of macrophages and enhancement of B cell function. The TH1 cell subtype is generally pro-inflammatory and IFNγ-secreting. There are regulatory T (Treg) cells that are involved in downregulation of TH1 cells, to decrease or terminate the immune response. It has been shown that upon repeated stimulation TH1 cells can switch into a Treg-like IL10-secreting anti-inflammatory phenotype. In the IL10-secreting Treg-like cells the microRNA 150 (miR-150) was found upregulated compared to IFNγ-secreting TH1 cells. Thus, miR-150 was believed to be a candidate in key regulation of the switch between the two phenotypes. Predicted target genes of miR-150 were identified using mRNA arrays investigating down-regulated genes in the IL10-secreting Treg-like subpopulation. In this thesis predicted targets of miR-150 were investigated using luciferase assays. Unfortunately no targets were identified. Upon isolation of IFNγ-secreting TH1 cells and Treg-like IL10-secreting cells, it was found that the ncRNA 886 (nc886) was upregulated in these activated cells, compared to resting TH cells. This indicates that nc886 has an important role in T cell activation. Nc886 has been shown to inhibit PKR activation in other cell types. The effect of nc886 on protein kinase R (PKR) was therefore investigated. PKR shuts down translation upon activation in response to viral double-stranded RNA or cellular stress. We showed that in an activated T cell phenotype nc886 is affecting PKR upon activation by dsRNA from HIV or synthetic origin. The PKR activation pattern is reversed in a resting T cell phenotype.
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Argent-Katwala, Mary Joan Grace. "The role of c Myb during T cell activation." Thesis, Institute of Cancer Research (University Of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289866.
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Madden, Jacqueline. "Flow cytometric assessment of T cell activation in asthma." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245048.
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Sharif-Paghaleh, Ehsan. "In vivo imaging of regulatory T cell mediated transplant tolerance." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/in-vivo-imaging-of-regulatory-t-cell-mediated-transplant-tolerance(4ee28e3c-431f-430f-9484-d22f030787b1).html.
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Regulatory T cells (Tregs) were identified several years ago and are key in controlling autoimmune diseases and limiting immune responses to foreign antigens. These cells have been used successfully in animal models first and more recently in the clinic to prevent Graft vs Host disease and transplant rejections. However, their locations in vivo, their migratory abilities and their in vivo survival have not been extensively investigated. Imaging of the human sodium/iodide symporter via Single Photon Emission Computed Tomography (SPECT) has been used as a reporter gene to image various cell types in vivo. It has several advantages over other imaging techniques including high sensitivity, it allows non-invasive whole body studies of viable cell migration and localisation over time and lastly it may offer the possibility to be translated to the clinic. The study presented in this thesis addresses whether SPECT/CT imaging can be used to visualise the migratory pattern and survival of Tregs in vivo. At first, CD4+ T cells were directly radiolabelled and were subsequently imaged in vivo to demonstrate that T cells can be imaged using NanoSPECT/CT. Then Treg lines derived from CD4+CD25+FoxP3+ cells \ were/ retrovirally transduced with a construct encoding for the human Sodium Iodide Symporter (NIS) and the fluorescent protein mCherry. NIS expressing self-specific Tregs were specifically radiolabelled in vitro with Technetium-99m pertechnetate (9 mTcC)4~) and exposure of these cells to radioactivity was shown not to affect cell viability, phenotype and Treg function. In addition adoptively transferred Treg-NIS cells were imaged in vivo in C57BL/6 (BL/6) mice by SPECT/CT using 99mTcO4". After 24 hours NIS expressing Tregs were observed in the spleen and their localisation was further confirmed by organ biodistribution studies and flow cytometry analysis. Later, Treg lines with direct or indirect alloantigen specificity were imaged in skin transplant models using the same technique. It was observed that adoptively transferred Tregs migrate to the site of transplant at earlytime points and then migrated to various lymph nodes. The data presented here suggests that SPECT/CT imaging can be utilised in preclinical imaging studies of adoptively transferred Tregs without affecting Treg function and viability thereby allowing longitudinal studies within disease models. Moreover, new insight into pattern of migration of Tregs was identified.
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Ruggero, Katia. "Role of microRNAs in T-cell activation and transformation by human T-cell Leukemia virus type 1." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422191.
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Human T-Lymphotropic virus type 1 (HTLV-1) is the causative agent of two distinct pathologies, adult T-cell leukemia/lymphoma (ATLL), an aggressive malignancy of mature CD4+ T-cells, and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), a demyelinating neurodegenerative disease. Despite intense study, many aspects of HTLV-1 replication, persistence and pathogenesis remain to be understood. The work described in the present thesis was aimed at defining the role of microRNAs (miRNAs) in HTLV-1 infection and ATLL pathogenesis.
We generated small RNA libraries from normal CD4+ cells (resting and stimulated) and two T-cell lines chronically infected with HTLV-1 (MT-2 and C91PL). Libraries were analyzed by 454 mass sequencing and data were processed through a series of computational steps to identify known and candidate new miRNAs for each library. Comparison of frequencies of known miRNAs in the different libraries led to the identification of 14 downregulated miRNAs and 4 upregulated species in infected cell lines vs. resting CD4+ cells, while 21 miRNAs were differentially expressed (16 downregulated, 5 upregulated) in stimulated compared to resting CD4+ cells. We validated the expression of some new miRNA candidates identified by bioinformatic analysis of the libraries through end point and quantitative RT-PCR. Two sequences mapped to the HTLV-1 genome, suggesting that the virus may produce its own miRNAs under certain conditions.
We examined the profiles of known miRNA expression in ATLL cells and normal resting and activated T CD4+ lymphocytes using microarrays. On the basis of miRNA expression, cluster analysis of ATLL samples and CD4+ controls showed that the resting controls were highly related to each other, while the tumor samples exhibited some heterogeneity. Statistical analysis revealed 6 upregulated and 21 downregulated miRNAs in ATLL cells compared to CD4+ T-cell controls. Several of the differentially expressed miRNAs identified in the libraries and by microarray analysis were validated by real time RT-PCR.
Since miRNA-mRNA interactions often result in degradation of the target mRNA, integration of results from target prediction programs with expression profiles for miRNAs and mRNAs can aid in identifying genuine mRNA targets. This approach was applied to miRNA and mRNA microarray data obtained for our ATLL and resting CD4+ samples. Potential targets for 12 miRNAs differentially expressed in ATLL cells were identified by integrating miRNA and mRNA expression profiles. Functional enrichment analysis of predicted targets revealed the presence of several genes belonging to the cAMP signalling pathway, which is known to be activated upon HTLV-1 transformation. We also investigated the role of miR-34a, consistently upregulated in ATLL samples and HTLV-1 infected cells lines. Knockdown of miR-34a in infected cell lines determined an increased in cell death, suggesting that miR-34a could play an important role in the expansion of HTLV-1 infected cells and thereby in ATLL development.Il virus T-linfotropico umano di tipo 1 (HTLV-1) è l’agente eziologico della leucemia/linfoma a cellule T dell’adulto (ATLL, adult T-cell leukemia/lymphoma) e della paraparesi spastica tropicale/mielopatia associata ad HTLV (TSP/HAM, Tropical spastic paraparesis/HTLV-associated myelopathy), una patologia degenerativa del sistema nervoso centrale. Recenti evidenze suggeriscono che i microRNA (miRNA) contribuiscano a questo processo di trasformazione mediata da HTLV-1. Le ricerche condotte nel corso del mio dottorato sono state mirate ad approfondire il ruolo dei microRNA (miRNA) nell’infezione di cellule T da parte di HTLV-1 e nella patogenesi dell’ATLL. Sono state realizzate librerie di cDNA di piccoli RNA, a partire da linfociti T CD4+ normali (resting e attivati) e da due linee cellulari cronicamente infettate con HTLV-1 (C91PL e MT-2). Le librerie sono state analizzate attraverso il sequenziamento di massa 454 e l’analisi bioinformatica delle sequenze ottenute ha permesso l’identificazione dei miRNA noti e nuovi miRNA candidati presenti in ciascuna libreria. Il confronto delle frequenze dei miRNA noti nelle diverse librerie ha evidenziato la presenza di 14 e 4 miRNA rispettivamente downregolati e upregolati nelle linee cellulari infettare rispetto ai linofociti T CD4+ resting, mentre 21 miRNA sono risultati differenzialmente espressi in linfociti T CD4+ stimolati in confronto ai linfociti T CD4+ resting (16 downregolati, 5 upregolati). L’espressione di diversi nuovi miRNA, individuati dall’analisi bioinformatica delle librerie, è stata validata attraverso RT-PCR end-point o RT-PCR quantitativa. Inoltre la nostra analisi ha rivelato nelle librerie da cellule infettate 2 sequenze che mappano in regioni trascritte del genoma di HTLV-1 e che potrebbero rappresentare dei miRNA virali. Attraverso l’impiego di microarray il profilo di espressione dei miRNA noti è stato analizzato in pazienti ATLL e in linfociti T CD4+ resting e stimolati. In base ai profili di espressione di miRNA ottenuti i campioni sono stati raggruppati in cluster che indicano una forte similitudine all’interno dei campioni di linfocititi T CD4+ resting, mentre i campioni di ATLL hanno profili di espressione di miRNA più eterogenei. L’analisi statistica ha evidenziato 21 miRNA downregolati e 6 upregolati nei pazienti ATLL vs linfociti T CD4+ resting. Diversi miRNA differenzialmente espressi identificati attraverso l’analisi delle librerie e dei microarray sono stati validati tramite RT-PCR quantitativa. Dal momento che l’interazione miRNA-mRNA spesso comporta la degradazione del messaggero bersaglio, l’analisi integrata dei risultati dei programmi di predizione di bersagli con i profili di espressione di miRNA e geni può aiutare nell’identificazione di target. Abbiamo applicato questo approccio ai dati di espressione di miRNA e geni ottenuti per i nostri campioni di ATLL e linfociti T CD4+ resting. Dall’integrazione dei profili di espressione di miRNA e mRNA sono stati identificati i target putativi per 12 miRNA differenzialmente espressi nei pazienti ATLL. L’arricchimento funzionale dei geni bersaglio predetti ha evidenziato la presenza di diversi geni coinvolti nella via di segnale di cAMP, noto per essere presente ad alti livelli in cellule trasformate da HTLV-1. Infine abbiamo indagato il significato funzionale di miR-34a, che risulta essere consistentemente upregolato in pazienti ATLL e linee cellulari infettate. Il silenziamento di miR-34a in linee cellulari infettate determina un aumento della morte cellulare, suggerendo che la deregolazione di questo miRNA possa svolgere un ruolo importante nell’espansione della popolazione di cellule infettate da HTLV-1 e quindi nello sviluppo dell’ATLL.
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Chen, Ye. "Induced regulatory T cells in transplantation tolerance." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:cffc275b-d32c-495e-a1da-55421a57e7e7.
Full textAbstract:
Induced regulatory T cells (iTreg) play an important role in the induction of tolerance to self and non-self antigens. Harnessing their suppressive potential has therapeutic implications for the treatment of autoimmune conditions and transplant rejection. Although the role of TGFβ-conditioned iTreg in natural and therapeutic tolerance is indisputable, their mechanism of action as well as factors that influence their function and stability in vivo remain unclear. Here it is shown that TGFβ-conditioning of T cells in the absence of any Foxp3 expression is insufficient for conferring a suppressive phenotype in vivo, whilst Foxp3 expression is sufficient to enable naïve T cells to become suppressive both in vitro and in vivo. Graft antigen was found to enhance the number of iTreg-derived Foxp3+ cells localising to the draining lymph nodes of recipients, and this was associated with histone modifications at the Foxp3 locus that suggested a stabilisation or 'affirmation' of Foxp3 expression. Finally, iTreg were shown to 'out-compete' naïve T cells in forming clusters with dendritic cells. Activated inflammatory T cells could also 'out-compete' naïve T cells. However, unlike activated T cells, iTreg did not activate interacting DCs to the same extent, and this may potentially be a mechanism of their action in vivo.
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Brignall, Ruth. "The single-cell and gene expression analysis of T cell activation and signalling." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/the-singlecell-and-gene-expression-analysis-of-t-cell-activation-and-signalling(d4f814bf-b4f7-4e23-8130-5ba4b9f38c13).html.
Full textAbstract:
Our immune system must be able to rapidly fight against pathogens, but at the same time be tightly regulated to prevent harmful autoimmune and inflammatory responses. This intricate balance is controlled in part by T lymphocytes. Therapies targeting T cells have the potential to revolutionise the ways in which inflammation and autoimmune diseases are treated. However, before this can be achieved, a better quantitative understanding of the molecular processes controlling the functions of these cells is required. T cell signalling is tightly regulated by a series of complex molecular networks, which converge on key transcription factors, including Nuclear Factor-κB (NF-κB), Nuclear Factor of Activated T cells (NFAT), and Activator Protein 1 (AP-1). Using a combination of single-cell time-lapse imaging, and genome-wide assays probing for chromatin accessibility and gene expression, this study provides a better understanding of the mechanisms underpinning T cell activation and signalling. One central tenet of T cell activation is that activation-associated gene expression is triggered by the binding of the cognate antigen to the T cell receptor (TCR), and enhanced by co-stimulatory receptors, including CD28, which act to augment TCR signalling. This study shows that activation- associated gene expression programmes (induced by calcium ionophore ionomycin and phorbol 12-myristate 13-acetate (PMA) in Jurkat T cells) are closely associated with specific chromatin landscapes. Further to this, data shown here indicate that the integration between TCR and co- stimulatory receptor signalling occurs at the chromatin level, and plays a pivotal role in regulating T cell activation. Using live-cell imaging, this study also shows that information about the diverse external signals received by T cells could be encoded within the dynamic nuclear translocations of key transcription factors. In particular, TCR signals appear to be processed by the duration of NFAT nuclear occupancy. TCR stimulation in the presence of a co-stimulatory signal resulted in the rapid nuclear import and export of NFAT proteins. In contrast, when TCR stimulation was applied without a co-stimulatory signal, prolonged nuclear occupancy of NFAT was observed. Further investigation suggested that the sustained activity of NFAT could confer a ‘signal memory’ within the TCR signalling network, thus providing a potential mechanism for preventing premature T cell turn-off during transient T cell-Antigen presenting cell interactions. This new detailed picture of T cell biology moves the field towards better therapeutic strategies for numerous diseases.
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Mahon, Robert Norman III. "Direct Inhibition of CD4+ T-cell Activation by Mycobacterium tuberculosis Cell Wall Glycolipids." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1275668686.
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