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1
Evans, Dean E. "CD40 Sustains T Cell Activation During Cognate Communication with Resting B Cells: a Dissertation." eScholarship@UMMS, 1998. http://escholarship.umassmed.edu/gsbs_diss/178.
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T and B-lymphocytes play an important role in an adaptive immune response. Communication between these two cells may result in either a humoral immune response or tolerance. Communication between T and B-lymphocytes involves a number of inducible cell surface molecules on both T and B-lymphocytes. It was the aim of this project to gain a greater understanding of the role of CD40 in the dynamic communication that occurs between naïve T-lymphocytes and resting B-lymphocytes during cognate communication. Because in vivo antigen specific T-lymphocytes are at low frequency, it is difficult to examine antigen-specific naïve T-lymphocytes. Thus, an in vitro system employing naïve antigen-specific T cell receptor (TCR) transgenic T cells and small resting B-lymphocytes that did not express CD40 was devised to examine the role of CD40 in cognate communication between naïve T-lymphocytes and resting B-lymphocytes.
Upon recognition of antigen on resting B-lymphocytes that expressed CD40, T-lymphocytes proliferated, expressed the activation antigens CD69 and CD25, and remained responsive to subsequent antigen challenge. In the absence of CD40, resting B-lymphocytes did not induce sustained proliferation or sustained expression of the activation markers CD69 and CD25 on naïve T-lymphocytes, and their recovery was decreased compared to naïve T-lymphocytes that recognized antigen on resting B-lymphocytes that expressed CD40. Naïve T-lymphocytes, however, remained responsive to subsequent antigen challenge after recognition of antigen on resting CD40-/- B-lymphocytes. Recognition of antigen on resting CD40-/- B-lymphocytes also resulted in increased recovery and antigen responsiveness of T-lymphocytes when compared to controls without antigen, The role of CD40 in sustaining activation of naïve T-lymphocytes may be unique to resting B-lymphocytes, since proliferation of naïve T-lymphocytes in response to dendritic cells that did not express CD40 was similar to proliferation of naïve T-lymphocytes in response to dendritic cells that expressed CD40. The mechanism by which CD40 sustained activation of naïve T-lymphocytes was investigated by examining the induction of various costimulatory molecules on resting CD40+/- and CD40-/- B-lymphocytes during cognate interaction with naive T-lymphocytes. Induction of B7-1, upregulation of CD44 and ICAM-1, and sustained but not initial induction of B7-2 required that CD40 be expressed on resting B-lymphocytes. Expression of B7-1 and CD44H was not required for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes. However, sustained expression of B7-2 was crucial for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes.
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Page, Theresa Helen. "Studies of rat cell surface activation antigens : molecular characterisation of the alpha and beta chains of the interleukin-2 receptor." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280535.
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DiSanto, James Philip. "Molecular events in human T cell activation : CD4, CD8 and the human Lyt-3 molecules /." Access full-text from WCMC, 1989. http://proquest.umi.com/pqdweb?did=745024391&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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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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Jellison, Evan Robert. "CD4 T Cell-Mediated Lysis and Polyclonal Activation of B Cells During Lymphocytic Choriomeningitis Virus Infection: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/349.
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CD4 T cells and B cells are cells associated with the adaptive immune system. The adaptive immune system is designed to mount a rapid antigen-specific response to pathogens by way of clonal expansions of T and B cells bearing discrete antigen-specific receptors. During viral infection, interactions between CD4 T cells and B cells occur in a dynamic process, where B cells that bind to the virus internalize and degrade virus particles. The B cells then present viral antigens to virus-specific CD4 T cells that activate the B cells and cause them to proliferate and differentiate into virus-specific antibody-secreting cells. Yet, non-specific hypergammaglobulinemia and the production of self-reactive antibodies occur during many viral infections, and studies have suggested that viral antigen-presenting B cells may become polyclonally activated by CD4 T cells in vivo in the absence of viral engagement of the B cell receptor. This presumed polyclonal B cell activation associated with virus infection is of great medical interest because it may be involved in the initiation of autoimmunity or contribute to the long-term maintenance of B cell memory.
In order to directly examine the interactions that occur between T cells and B cells, I asked what would happen to a polyclonal population of B cells that are presenting viral antigens, if they were transferred into virus-infected hosts. I performed these studies in mice using the well-characterized lymphocytic choriomeningitis virus (LCMV) model of infection. I found that the transferred population of antigen-presenting B cells had two fates. Some antigen-expressing B cells were killed in vivo by CD4 T cells in the first day after transfer into LCMV-infected hosts. However, B cells that survived the cytotoxicity underwent a dynamic polyclonal activation manifested by proliferation, changes in phenotype, and antibody production.
The specific elimination of antigen-presenting B cells following adoptive transfer into LCMV-infected hosts is the first evidence that MHC class II-restricted killing can occur in vivo during viral infection. This killing was specific, because only cells expressing specific viral peptides were eliminated, and they were only eliminated in LCMV-infected mice. In addition to peptide specificity, killing was restricted to MHC class II high cells that expressed the B cell markers B220 and CD19. Mice depleted of CD4 T cells prior to adoptive transfer did not eliminate virus-specific targets, suggesting that CD4 T cells are required for this killing. I found that CD4 T cell-dependent cytotoxicity cannot be solely explained by one mechanism, but Fas-FasL interactions and perforin are mechanisms used to induce lysis.
Polyclonal B cell activation, hypothesized to be the cause of virus-induced hypergammaglobulinemia, has never been formally described in vivo. Based on previous studies of virus-induced hypergammaglobulinemia, which showed that CD4 T cells were required and that hypergammaglobulinemia was more likely to occur when virus grows to high titer in vivo, it was proposed that the B cells responsible for hypergammaglobulinemia may be expressing viral antigens to virus-specific CD4 T cells in vivo. CD4 T cells would then activate the B cells. However, because the antibodies produced during hypergammaglobulinemia are predominantly not virus-specific, nonvirus-specific B cells must be presenting viral antigens in vivo.
In my studies, the adoptively transferred B cells that survived the MHC class II-restricted cytotoxicity became polyclonally activated in LCMV-infected mice. Most of the surviving naïve B cells presenting class II MHC peptides underwent an extensive differentiation process involving both proliferation and secretion of antibodies. Both events required CD4 cells and CD40/CD40L interactions to occur but B cell division did not require MyD88-dependent signaling, type I interferon signaling, or interferon γ signaling within B cells. No division or activation of B cells was detected at all in virus-infected hosts in the absence of cognate CD4 T cells and class II antigen. B cells taken from immunologically tolerant donor LCMV carrier mice with high LCMV antigen load became activated following adoptive transfer into LCMV-infected hosts, suggesting that B cells can present sufficient antigen for this process during a viral infection. A transgenic population of B cells presenting viral antigens was also stimulated to undergo polyclonal activation in LCMV-infected mice. Due to the high proportion of B cells stimulated by virus infection and the fact that transgenic B cells can be activated in this manner, I conclude that virus-induced polyclonal B cell activation is independent of B cell receptor specificity. This approach, therefore, formally demonstrates and quantifies a virus-induced polyclonal proliferation and differentiation of B cells which can occur in a B cell receptor-independent manner.
By examining the fate of antigen-presenting B cells following adoptive transfer into LCMV-infected mice, I have been able to observe dynamic interactions between virus-specific CD4 T cells and B cells during viral infection. Adoptive transfer of antigen-presenting B cells results in CD4 T cell-mediated killing and polyclonal activation of B cells during LCMV infection. Studies showing requirements for CD4 T cells or MHC class II to control viral infections must now take MHC class II-restricted cytotoxicity into account. Polyclonal B cell activation after viral infection has the potential to enhance the maintenance of B cell memory or lead to the onset of autoimmune disease.
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Shaulov, Angela. "The roles of inflammation and antigen in CD8 T cell expansion and memory differentiation /." Thesis, Connect to this title online; UW restricted, 2008. http://hdl.handle.net/1773/8328.
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Li, Cheng-Rui Michael. "The Role of Tec Kinases in CD4+ T Cell Activation: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/3.
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The Tec family tyrosine kinases Itk, Tec and Rlk are expressed in T cells. Previous studies have established that these kinases are critical for TCR signaling, leading to the activation of PLCγ1. To further understand the functions of Tec kinases in T cell activation, we took three different approaches. First, we performed a thorough analysis of CD28-mediated signaling events and functional responses with purified naïve T cells from Itk-/- mice and a highly controlled stimulation system. Data from this set of studies definitively demonstrate that CD28 costimulation functions efficiently in naïve CD4+ T cells in the absence of Itk. Second, in order to further study the functions of Tec kinases in vivo, we generated transgenic mouse lines expressing a kinase-dead (KD) mutant of Tec on the Itk-/-Rlk-/- background, hoping to study mice that are functionally deficient for all three Tec kinases. The results hint the importance of the Tec kinases in T cell development and/or survival. Finally, in order to identify potential transcriptional targets of Itk, we used microarray technology to compare global gene expression profiles of naïve and stimulated Itk-/- versus Itk+/- CD4+ T cells. This analysis provided a short list of differentially expressed genes in Itk-/- versus Itk+/- CD4 T cells, providing a starting point for further studies of Itk in T cell activation. Collectively, these studies clarified the role of Itk in CD28 signaling, revealed some unexpected aspects of Tec family kinases in T cells, and indicated potential targets of Itk-dependent signaling pathways in T cells.
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Delli, Joe. "Coreceptor and costimulatory signals organize proteins within the immunological synapse and augment proximal T cell signaling events /." Connect to full text via ProQuest. IP filtered, 2006.
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Thesis (Ph.D. in Immunology) -- University of Colorado, 2006.Typescript. Includes bibliographical references (leaves 277-285). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Forsgren, Stina. "Mechanisms of lymphocyte selection in physiology and autoimmune pathology." Doctoral thesis, Umeå universitet, Molekylärbiologi (Teknat- och Medfak), 1991. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100593.
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Hernandez, Maria Genevieve H. "The Role of CD40 in Naïve and Memory CD8+ T Cell Responses: a Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/346.
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Stimulation of CD40 on APCs through CD40L expressed on helper CD4+ T cells activates and “licenses” the APCs to prime CD8+ T cell responses. While other stimuli, such as TLR agonists, can also activate APCs, it is unclear to what extent they can replace the signals provided by CD40-CD40L interactions. In this study, we used an adoptive transfer system to re-examine the role of CD40 in the priming of naïve CD8+ T cells. We find an approximately 50% reduction in expansion and cytokine production of TCR-transgenic T cells in the absence of CD40 on all APCs, and on dendritic cells in particular. Moreover, CD40-deficient and CD40L-deficient mice fail to develop endogenous CTL responses after immunization and are not protected from a tumor challenge. Surprisingly, the role for CD40 and CD40L are observed even in the absence of CD4+ T cells; in this situation, the CD8+T cell itself provides CD40L. Furthermore, we show that although TLR stimulation improves T cell responses, it cannot fully substitute for CD40.
We also investigated whether CD40-CD40L interactions are involved in the generation, maintenance, and function of memory CD8+ T cells. Using a virus infection system as well as a dendritic cell immunization system, we show that the presence of CD40 on DCs and other host APCs influences the survival of activated effector cells and directly affects the number of memory CD8+ T cells that are formed. In addition, memory CD8+ T cell persistence is slightly impaired in the absence of CD40. However, CD40 is not required for reactivation of memory CD8+ T cells. It seems that CD40 signals during priming also contribute to memory CD8+ T cell programming but this function can be independent of CD4+T cells, similar to what we showed for primary responses.
Altogether, these results reveal a direct and unique role for CD40L on CD8+ T cells interacting with CD40 on APCs that affects the magnitude and quality of primary as well as memory CD8+ T cell responses.
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Orchard, Guy Edward. "A study of activation antigens involved in the pathological mechanisms and pathways of cutaneous malignant disease with particular emphasis on cutaneous T cell lymphoma and malignant melanoma." Thesis, University of Westminster, 2010. https://westminsterresearch.westminster.ac.uk/item/90750/a-study-of-activation-antigens-involved-in-the-pathological-mechanisms-and-pathways-of-cutaneous-malignant-disease-with-particular-emphasis-on-cutaneous-t-cell-lymphoma-and-malignant-melanoma.
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The investigation of dermatological conditions embraces the concept of a clinicopathological correlation. The studies into cutaneous T cell lymphoma (CTCL) and malignant melanoma (MM), presented here involved predominantly immunocytochemical procedures and relate to the investigations into AP-1 protein expression in CTCL and melanocyte activation antigens in MM. Results: Findings indicate that expression of AP-1 proteins differs not only according to type of CTCL but also according to stages of tumour progression. In MM activation antigen expression varies with tumour metastasis. Consideration of the role of techniques in terms of sensitivity and specificity form a pivitol component in the evaluation of tumour antigen expression.
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Misztela, Dominika. "The differential effects of CD80 and CD86 in helper T lymphocyte activation." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670088.
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Simmons, Daimon P. "Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278.
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Bonnard, Madeleine. "A novel role for CD4 in antigen-mediated T-cell activation /." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=68156.
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A number of T-cell membrane molecules influence the outcome of antigen recognition by TCR/CD3 complex. CD4, by virtue of its non-covalent association with the protein tyrosine kinase lck has the capacity to enhance TCR$ alpha beta$ signalling. The extracellular domain of CD4 interacts with monomorphic determinants of Major Histocompatibility complex class-II molecules such that antigen presented in association with MHC class-II to CD4$ sp+$ T-cells results in the coaggregation of CD4 and TCR/CD3, thus juxtaposing lck and the antigen-receptor complex. Anti-CD4 antibodies abrogate both antigen and anti-TCR-induced T-cell activation. Studies using antigen specific T-cell clones that express either no CD4, wild type CD4 or mutated CD4 that cannot associate with lck (Db CYS) indicate that CD4 sequesters the majority of cellular lck and when not coaggregated with TCR/CD3, prevents the generation of prerequisite signals.Results presented in this thesis indicate that while CD4-associated lck is providing prerequisite signals for TCR/CD3 signalling, the contribution of CD4 must be more than simply providing a shuttle for lck. Specifically, anti-CD4 inhibits the antigen response of Db CYS CD4-expressing clones. This result cannot be accounted for either by CD4 sequestration of lck, or reduction of avidity of the interaction between the T-cell and the antigen presenting cell, since CD4$ sp-$ variants exhibit an antigen response comparable to that of CD4$ sp+$ variants. Rather, they suggest a novel role for the ectodomain of CD4 in antigen-induced T-cell activation.
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Sandalova, Elena. "Regulation of the pro-apoptotic protein bim by T cell receptor triggering in human T cells /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-041-1/.
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Bujdoso, R. "The role of antigen presenting cells in the activation of T cells." Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303811.
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Tao, Xiang. "Mechanisms of T Cell-mediated Macrophage Activation: Role of Antigen Specific and Antigen Nonspecific Cognate Interactions." Digital Commons @ East Tennessee State University, 1993. https://dc.etsu.edu/etd/2803.
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Macrophages play an important role in host antimicrobial immunity and in non-septic inflammatory reactions. Most studies on macrophage activation have focused on the roles of the T cell-produced cytokine, interferon-$\gamma$ (IFN$\gamma)$ and bacterial product, lipopolysaccharide (LPS). T cell-macrophage interaction is a critical step in initiating both specific and nonspecific immune responses to antigenic stimulation. The current study examines the role of cognate T cell-macrophage interaction in activation of macrophage effector functions and induction of macrophage early activation gene expression. Viable resting T$\sb{\rm H}$2 clone cells can activate IFN$\gamma$-primed macrophages to produce reactive nitrogen intermediates (RNI) or express cytostatic activity. The activating signal is mediated by cognate membrane contact between T cells and macrophages as evidenced by the ability of paraformaldehyde fixed anti-CD3-activated T$\sb{\rm H}$2 cells or plasma membranes isolated from the activated T cells to activate the IFN$\gamma$-primed macrophages. In contrast to the antigen-specific interaction of macrophages with viable resting T$\sb{\rm H}$2 cells, the activation of IFN$\gamma$-primed macrophages by fixed activated T$\sb{\rm H}$2 cells or by membranes from activated T$\sb{\rm H}$2 cells does not display antigen specificity. Fixed resting T$\sb{\rm H}$2 cells or plasma membranes isolated from the resting T cells can not activate the IFN$\gamma$-primed macrophages. Similar results are obtained with use of fresh splenic T cells to induce macrophage RNI production and cytostasis. Monoclonal antibody against CD4, which presumably blocks the interaction between CD4 (a co-receptor of T cell receptor) and class II MHC molecules on macrophages, inhibits significantly the activation of IFN$\gamma$-primed macrophages by viable resting T$\sb{\rm H}$2 cells but does not inhibit the ability of fixed activated T$\sb{\rm H}$2 cells to activate the macrophages. To examine the intracellular events in macrophages initiated by the cognate signaling, the expression of a panel of macrophage early activation genes, c-Myc, c-Fos, JE, IP10, D3, TNF$\alpha$ and IL-$\alpha$, are analyzed by dot blot hybridization. Plasma membranes from activated T$\sb{\rm H}$2 cells induce the expression of all these genes in macrophages stimulated for 1-4 hour. In contrast, the plasma membranes from resting T$\sb{\rm H}$2 cells are unable to induce the expression of most of the genes examined. These results suggest that the T cell-macrophage interaction involves reciprocal activation of both cells--an antigen specific activation of the T cells which results in the acquisition of T cell membrane components involved in antigen nonspecific activation of the macrophages. The nature of those T cell membrane components involved in cognate signaling of macrophage is currently being investigated.
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Adamson, Janet. "Structure and function of the platelet and T-cell activation antigen-1 (PTA1)." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367096.
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Dugger, Kari J. "Visualizing the function and migration of T cells." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2007p/dugger.pdf.
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Wei, Cheng-Hong. "Regulation of T cell activation and death by the affinity of TCR for peptide/MHC complexes /." Stockholm : Karolinska Univ. Press, 2002. http://diss.kib.ki.se/2002/91-7349-239-6.
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Getahun, Andrew. "Antibody Feedback Regulation : From Epitope Masking to T Helper Cell Activation." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4580.
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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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Shao, Mei. "Optimize the generation and depletion of alloreactive T cells for cellular therapy." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1135261379.
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Gibson, Andrew. "Utilisation of an in vitro T-cell priming assay to characterise the effects of co-inhibitory signalling on the activation of antigen-specific T-cells." Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/3001347/.
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Hypersensitivity denotes a form of immune-mediated adverse reaction associated with a high degree of morbidity and mortality. Due to a lack of animal models, research has focussed on patient lymphocytes ex vivo. However, such studies bypass investigation of naïve T-cell activation. Subsequently, in vitro assays to assess the priming of healthy donor naïve T-cells have been developed to facilitate the discrete analysis of primary and secondary T-cell responses. While these assays have been used to assess the association of specific HLA alleles with hypersensitivity, for most drugs, the majority of individuals who are positive for an HLA risk allele do not develop a reaction. Thus, predisposition to hypersensitivity is likely mediated by other parameters. As polymorphisms in co-inhibitory pathways are associated with dysregulated immune responses, we first investigated the role of these pathways during the drug antigen (SMX-NO)-specific activation of T-cells. Antibody-mediated blockade of PD-L1 enhanced the activation of SMX-NO-primed naive, but not memory, T-cells. In comparison, inclusion of PD-L2 block had no effect, but in combination with PD-L1 block effectively dampened the enhanced T-cell activation seen with PD-L1-block alone. In comparison, inclusion of CTLA4 block enhanced the proliferative response of antigen-stimulated naive, but also memory T-cells, suggesting a greater regulatory role for CTLA4 than PD-1 during secondary T-cell responses. Blockade of TIM-3 had no effect on T-cell activation. Further investigation focussed on the kinetics of receptor expression. While all receptors were upregulated on naive and memory T-cells during the 3 week culture after antigen exposure, PD-1 was upregulated at earlier time points than CTLA4 and TIM-3 indicating a differential role for these receptors during early and late stage T-cell activation. Moreover, CTLA4 expression was induced in response to antigen far less on CD4+ T-cells suggesting that CTLA4 has a greater regulatory role during the drug antigen-specific activation of CD8+ T-cells. High expression of individual co-inhibitory receptors including PD-1 has previously been associated with exhausted T-cells, while other studies indicate that these cells are highly functional. To address this, we compared receptor expression with T-cell clone function. To assess function, we investigated the role of the newly identified Th17 and Th22 subsets in these responses. A range of Th1/Th2 cytokines were secreted in response to SMX-NO including IFN-γ, IL-13, and IL-5. While no IL-17 was detected, 50% of clones secreted IL-22. Further analysis uncovered two distinct antigen-responsive T-cell subsets that secrete Fas-L/IL-22 or granzyme B, the presence of which was confirmed utilising cells from SMX-hypersensitive patients. This is the first data to show production of IL-22 alongside IFN-γ by antigen-specific T-cells from drug-hypersensitive patients. Analysis of the level of individual co-inhibitory receptor expression found no correlation with T-cell proliferative capacity or secretion of cytokines/cytolytic molecules. Both SMX and SMX-NO, stimulate T-cells from hypersensitive patients. 9/10 healthy donors respond to SMX-NO, while only 30% respond to SMX in vitro. These observations were made using a whole lymphocyte population and thus we utilised an in vitro T-cell priming assay, whereby naïve or memory T-cells from healthy donors are stimulated with drug-antigen using mature dendritic cells, to assess the T-cell origins of antigen-responsive cells. Both naïve and memory T-cells were activated by SMX-NO in all donors. Although SMX failed to induce proliferative responses, 2/3 donors displayed SMX-induced IL-13 secretion. SMX and SMX-NO-responsive clones were subsequently generated from these donors from naïve and memory T-cell cultures indicating that the priming of naïve T-cells and the re-activation of memory T-cells has a role in the onset of SMX-induced hypersensitivity. As these responses were detected using cells from drug-naïve donors, the memory T-cell responses are likely a result of cross-reactivity with T-cells primed to an undetermined peptide antigen. Our data are the first to show that both hapten and parent drug can stimulate pre-existing memory T-cells from drug-naïve donors. PPD, a compound found in dyes used for hair colouring, is associated with ACD. Both PPD and a downstream oxidation product, BB, activate T-cells in allergic patients. Thus we used an in vitro T-cell priming assay to assess the propensity of PPD and BB to activate naïve and memory T-cells from healthy donors, and compared responses to those characterised from allergic patients. 105 PPD- and 122 BB-responsive T-cell clones were generated from five allergic patients. More than 90% of patient BB-clones were CD4+, and all lacked cross-reactivity. In contrast, certain PPD-clones cross-reacted with BB, and 37.5% expressed CD8 promoting PPD as the central driving force behind the allergic reaction. However, upon utilising cells from healthy donors, neither naïve nor memory T-cells were activated by PPD suggesting the lack of important susceptibility factors. In comparison, both naïve and memory T-cells were activated by BB, which similarly to patients displayed a lack of cross-reactivity and secreted a similar panel of cytokines including IFN-γ, IL-13, and IL-22. In conclusion, the similar findings between drug and chemical antigen-responsive T-cells generated using an in vitro T-cell priming assay and those from patients highlight the promising use of this assay in the investigation of these responses. Indeed, the future definition and inclusion of (a) susceptibility factors and (b) the peptide-antigens responsible for naive T-cell priming will form a promising platform for the safe screening of drugs.
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Chouaki-Benmansour, Nassima. "Analyse du rôle des PIP2 dans l'initiation de la signalisation TCR et l'activation lymphocytaire." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4052.
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L'activation des lymphocytes T est un événement fondamental de la réponse immunitaire adaptative. Elle est déclenchée par la transduction du signal médiée par le complexe TCR/CD3.Le mécanisme de déclenchement du signal via le TCR reste, mal compris. Mon projet de thèse vise à examiner la contribution des PI(4,5)P2 dans le mécanisme du déclenchement du signal TCR. L'expression ectopique d'une phosphatase spécifique de PIP2 a permis de réduire de 50% les PI(4,5)P2 membranaires. L'analyse du profil de phosphorylations spécifiques des tyrosines montre que l'expression ectopique de cette 5-phosphatase augmente les événements de phosphorylation à l'état basal comparés à des conditions analogues pour des cellules contrôles. En revanche, alors que suite à l'engagement du TCR par le complexe MHC-peptide indépendamment du co-récepteur CD4 nous observons une augmentation des phosphorylations, l'activation par le complexe MHC-peptide CD4 dépendant semble affectée. Nous avons analysé la contribution des PI(4,5)P2 dans la dynamique membranaire du TCR grâce à la technique svFCS. PIP2 peuvent jouer un rôle essentiel dans la régulation de la dynamique latérale du TCR à la membrane plasmique. Enfin, nous avons observé que l'inhibition par la néomycine (aminoglycoside qui en tant que polycation peut se lier et neutraliser le groupement anionique de PI(4,5)P2), aboutit à des changements similaires dans la dynamique membranaire du TCR et la régulation proximale dans des cellules T primaires murines CD4+. Ensemble, nos données révèlent le rôle régulateur fondamental de PI(4,5)P2 dans la dynamique membranaire du TCR et de CD4, pour le contrôle de l'initiation des voies de signalisation du TCRPI(4,5)P2 plays important roles in a large spectrum of membrane-based cellular activities . It is therefore surprising that it is currently not known if PI(4,5)P2 is also involved in the T cell receptor (TCR) signal transduction mechanism. We investigate here the role of PI(4,5)P2 in the regulation of the TCR membrane dynamics and signaling initiation using a combination of biophysical, biochemistry and cell biology approaches. Ectopic expression of the Inp54p, a 5-phophatase that hydrolyzes PI(4,5)P2 into PI(4)P, with a membrane targeting signal specifically decreased by 50% of the PI(4,5)P2 in a CD4+ T cell hybridoma. Interestingly, we observed that this decrease caused modified TCR (and CD4 co-receptor) dynamics in the plasma membrane. The lateral diffusion switched from a regime dominated by dynamic partitioning in the cholesterol- and sphingolipid-dependent nanodomains into one dominated by dynamic partitioning in the actin cytoskeleton-assisted nanodomains. This switch was associated with a change in activation of the TCR and proximal signaling pathways both at the basal level and upon stimulation. Upon pMHC engagement, the CD4-independent activation of the TCR signaling pathways was found significantly augmented while that of CD4-dependent was affected. We further provided evidence for the involvement of PI(4,5)P2 in the Finally, we found that inhibition of interactions between PI(4,5)P2 and endogenous proteins with neomycin resulted in the modified TCR membrane dynamics and proximal signaling in primary murine CD4+ T cells. Altogether, our data reveal that PI(4,5)P2 is crucially involved in the control of the activation of TCR early signaling pathways
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Siracusa, Francesco. "Maintenance and re-activation of antigen-specific CD8+ and CD4+ memory T lymphocytes in the bone marrow." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19335.
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Das Knochenmark (BM) beherbergt wesentliche Komponenten des adaptiven Immunsystems, die einen langfristigen Schutz gegen wiederkehrende Pathogene vermitteln können, sodass es sich als Reservoir für ein immunologisches Gedächtnis qualifiziert. Neben langlebiger Antikörper-produzierender Plasmazellen bleiben auch Antigen (Ag)-spezifische CD8+ und CD4+ T-Gedächtniszellen dauerhaft im Knochenmark erhalten, auch wenn sie in den sekundären lymphoiden Organen (SLOs) und im Blut abwesend sind. Es wird angenommen, dass diese T-Gedächtniszellen bei erneutem Kontakt mit den gleichen systemischen Pathogenen schnell reagieren können. Allerdings sind die biologischen Mechanismen für ihre langfristige Aufrechterhaltung immer noch umstritten und demnach ungeklärt. Unklar ist auch, wie die T-Gedächtniszellen des Knochenmarks bei erneuter Konfrontation mit demselben Antigen reagieren. Hier wird dieser Frage begegnet, indem durch klassiche Immunisierung mit definieren Antigenen eine stabile Population Ag-spezifischer CD8+ und CD4+ T-Gedächtniszellen im Knochenmark erzeugt wird.The bone marrow (BM) harbors critical components of the adaptive immune system being able to provide long-lasting protection against previously encountered pathogens, thus qualifying as a reservoir of immunological memory. In addition to long-lived antibody producing plasma cells, antigen (Ag)-specific CD8+ and CD4+ memory T lymphocytes are maintained long-term in the BM even when they are absent from secondary lymphoid organs (SLOs) and blood. Those memory T cells are thought to respond fast upon re-encounter of systemic pathogens. However, the biological mechanisms behind their long-term maintenance in the BM are still a matter of debate and thus remain unclear. Similarly, it is also unclear how the memory T cells of the BM react to antigenic re-challenge. Here we address these issues by generating a stable pool of Ag-specific CD8+ and CD4+ memory T lymphocytes in the BM by classical immunizations with defined antigens.
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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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Eickmeier, Ira. "Relevance of the activation and migration patterns of CD8 T cells for the development of immune-mediated liver injury." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/17032.
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Die initialen immunologischen Prozesse, die zur Entwicklung autoimmuner Lebererkrankungen führen, sind weitgehend unbekannt. Deshalb wurden in dieser Arbeit die Antigenpräsentation, die Migration sowie der Phänotyp in vivo aktivierter CD8 T-Zellen in der Leber anhand eines Mausmodells der autoimmunen Hepatitis untersucht. Es konnte gezeigt werden, dass hepatische dendritische Zellen an der Entstehung von CD8 Effektor-T-Zellen und an der Inflammation der Leber beteiligt sind. Kupffer-Zellen dagegen nehmen im autoimmunen Kontext in der Leber eine tolerogene Funktion ein. Die in vivo in der Leber aktivierten CD8 T-Zellen zeigten spezifische Oberflächenmarker und ein ungewöhnliches Migrationsverhalten. So wurde zum einen mit Neuropilin-1 ein weitgehend unbekannter Oberflächenmarker identifiziert, zum anderen spricht die Expression von bekannten Markern, die den Aktivierungsstatus der CD8 T-Zellen definieren, für einen hybriden Phänotyp. Sie besitzen sowohl Charakteristika von naiven CD8 T-Zellen als auch von Effektorzellen, eine Eigenschaft, die auch bei zentralen Gedächtniszellen gefunden wird. In der Leber aktivierte CD8 T-Zellen können nicht nur proinflammatorische Zytokine ausschütten und somit eine Inflammation in der Leber auslösen, sondern sind außerdem in der Lage durch Lymphknoten zu zirkulieren. Dagegen ist ihnen der Zugang zum Darm verwehrt, womit eine direkte regulatorische Funktion im Darm ausgeschlossen werden kann. Obwohl auf in der Leber aktivierten CD8 T-Zellen spezifische Adhäsionsmoleküle identifiziert wurden, existiert keine exklusive gewebespezifische Migration in die Leber, wie sie etwa für im Darm aktivierte CD8 T-Zellen nachgewiesen wurde. Im darmassoziierten lymphatischen Gewebe aktivierte CD8 T-Zellen akkumulieren in der Leber und tragen möglicherweise zur Schädigung der Leber im Rahmen chronisch entzündlicher Darmerkrankungen bei. Diese Arbeit trägt somit zum besseren Verständnis der Entstehung autoimmuner Prozesse in der Leber bei.Initial immunological processes leading to autoimmune liver diseases are largely unknown. Therefore this thesis analyzed the antigen presentation, the migration as well as the phenotype of in vivo activated CD8 T cells in the liver by employing a mouse model for autoimmune hepatitis. It was shown that hepatic dendritic cells are effective antigen-presenting cells, which contribute to the induction of functional effector CD8 T cells in the liver and hepatitis. In contrast, Kupffer cells have a tolerogenic role during autoimmune processes in the liver. CD8 T cells that were in vivo activated in the liver display specific surface markers and unusual migration patterns. On the one hand an unusual surface molecule Neuropilin-1 was identified, on the other hand expression of well-known markers defining the activation-status of CD8 T cells suggests a hybrid phenotype. They reflect aspects of naive and effector T cells, characteristics also found on central memory T cells. Liver-primed CD8 T cells do not only produce pro-inflammatory cytokines leading to hepatitis, but they also retain their ability to circulate through lymph nodes. However, they have no access to the gut, which suggests that a direct regulatory function in the gut can be excluded. Although specific adhesion molecules on CD8 T cells activated in the liver were identified, no exclusive tissue-specific migration into the liver exists, as was shown for CD8 T cells primed in the gut. CD8 T cells activated in the gut-associated lymphoid tissue accumulate in the liver, in principle enabling them to induce liver pathology in the context of inflammatory bowel disease. Thus, the here described findings contribute to the understanding of initial immunological processes in autoimmune liver diseases.
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Moreau, Hélène. "Regulation and signaling properties of T cell immunological synapses and kinapses in vivo." Paris 7, 2013. http://www.theses.fr/2013PA077039.
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L'activation des cellules T repose sur leurs interactions avec des cellules présentatrices de l'antigène CPA au cours desquelles le récepteur des cellules T TCR reconnaît le peptide antigénique AG fixé sur les molécules du complexes majeur d'histocompatibilité exprimées à la surface de la CPA. La visualisation des T et des CPA in vivo a révélé l'hétérogénéité des contacts T-CPA qui peuvent être stables (synapses) ou dynamiques (kinapses). La contribution de ces différentes interactions n'est pas établie. Nous avons cherché à comprendre comment les T sentent leur Ag in vivo et couplent motilité et activation. Nous avons développé la Cytométrie Dynamique In situ Disc, une méthode combinant les avantages de l'imagerie intravitale et de la cytométrie de flux. Le DISC nous a permis de visualiser simultanément le comportement des T et le signal TCR in vivo. Nous avons montré que les seuils d'affinité de l'Ag contrôlant la mobilité des T et le signal TCR sont distincts. Nous avons établi une hiérarchie des modes de reconnaissance de l'Ag : les synapses associées au signal TCR le plus fort, les kinapses associées à un signal robuste et les kinapses associées à un signal faible. Nos résultats suggèrent aussi que la détection d'Ag d'affinité faible à intermédiaire provoque une décélération des T en induisant un changement de mode de migration de manière calcium indépendante. Ce mécanisme pourrait expliquer le comportement kinapse. Les Ag de forte affinité fournissent des signaux additionnels calcium-dépendants qui induisent l'arrêt complet des T et l'établissement de synapses. Cette diversité de modes de reconnaissance de l'Ag oblige à repenser le processus d'activation TT cell activation relies on interactions with antigen presenting cells (APCs) during which the T cell receptor (TCR) recognizes antigenic peptide on Major Histocompatibility Complex molecules (pMHC) displayed on the surface of the APC. Imaging T cells and APCs in vivo revealed that T cell- APC contacts can either be very stable (synapses) or more dynamic and transient (kinapses). However, the respective contribution of these different interactions bas not been fully elucidated. We aimed at better understanding how T cells sense their cognate antigen in vivo and couple their motile behavior with the collection of activation signals. To this end, we introduced Dynamic In Situ Cytometry (DISC) a methodology combining intravital imaging and flow cytometry. DISC allowed us to simultaneously visualize T cell behavior and TCR signaling in vivo. With this approach, we found that different thresholds of antigen affinity controlled T cell dynamics and TCR signaling. We established a hierarchy of antigen recognition modes: synapses with thé strongest TCR signais, kinapses with robust signaling, and kinapses with weak signaling. Furthermore, we provide evidence that detection of low to intermediate affinity ligands induces T cell deceleration by promoting a calcium-independent switch of migration mode. This mechanism may underlie the kinapse-like behavior and promote further scanning of the microenvironment. Additional calcium-dependent signals are provided by high affinity ligand and induce complete T cell arrest and the establishment of a bona fide synapse. Such diversity in the modes of antigen recognition forces us to reconsider the process of T cell activation
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Deeg, Janosch A. [Verfasser], and Joachim P. [Akademischer Betreuer] Spatz. "Modulation of T cell Activation with Nano- and Micronanopatterned Antigen Arrays / Janosch A. Deeg ; Betreuer: Joachim P. Spatz." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1177810859/34.
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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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El, Sayed Rania. "ROLE OF FDCs AND FDC ACTIVATION IN PROMOTING HUMORAL IMMUNITY INCLUDING RESPONSES TO T-DEPENDENT ANTIGENS IN THE ABSENCE OF T CELLS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1927.
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Follicular dendritic cells (FDCs) reside in primary B-cell follicles and in the light zones of germinal centers (GCs) in secondary follicles, where their dendrites interdigitate forming extensive networks intimately interacting with B-cells. In GCs, FDCs can be found at the edges attached to the supporting reticular fibers. They trap and arrange immune complexes (ICs) in vivo and in vitro in a periodic manner with 200–500Å spacing and provide both antigen-specific and non-specific accessory signals to B-cells. FDCs exist in resting and activated states, with two characteristically different phenotypes. In their activated state, FDCs upregulate the expression of accessory molecules and cytokines important in the FDC-B cell interaction in GCs. We sought to determine the mechanisms influencing the transition of FDCs from a resting to an activated state in GCs and their impact on T-cell dependent (TD) and independent (TI)-GC reactions (GCRs). We found that IC-FDC interactions via FDC-FcgammaRIIB induce the upregulation of FDC-FcgammaRIIB, -ICAM-1, and -VCAM-1, at both the protein and mRNA levels. We also reported for the first time the expression of TLR-4 on FDCs. Moreover, engagement of FDC-TLR4 with LPS activated NF-kappaB, up-regulated expression of important FDC-accessory molecules, including FcgammaRIIB, ICAM-1, and VCAM-1, and enhanced FDC accessory activity in promoting recall IgG responses. Moreover, IC-activated FDCs produced IL-6 and FDC-IL-6 promoted GCRs, somatic hypermutation (SHM) and IgG production. Further, we reported that binding of FDCs to collagen coated surfaces induced restoration of their dendritic processes and networks in vitro. In addition, we designed an FDC-supported in vitro model capable of induction and assessment of primary human antibody responses to protein antigens characterized by class-switching and affinity maturation. Uniquely, we generated TI immune responses to TD protein Ags in the complete absence of T cell help in vivo and in vitro. In the presence of FDC-associated second signals such as BAFF and C4BP, FDC- FcgammaRIIB-periodically trapped-ICs induced the production of Ag-specific IgM, GC-development and plasmablast-differentiation in anti-Thy-1-pretreated nude mice. Purified murine and human B cells cultured in vitro with IC-bearing FDCs also showed the production of antigen–specific IgM within just 48 h.
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Waiczies, Sonia. "Modulation of human antigen-specific T-cell response therapeutic implications for multiple sclerosis /." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969681844.
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Hokello, Joseph Francis. "The Individual Contribution of Transcription Factors Mobilized Following T-cell Receptor (TCR) or Mitogenic Activation in the Reactivation of HIV from Latency." Cleveland, Ohio : Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1267065851.
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Peterson, Karin E. "The role of secondary signaling in experimental autoimmune thyroiditis." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9904865.
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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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Dübbel, Lena [Verfasser], Karl-Wilhelm [Akademischer Betreuer] Koch, and Edwin [Akademischer Betreuer] Bremer. "Characterization of the novel negative checkpoint regulator V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA) on Antigen Presenting Cells / Lena Dübbel ; Karl-Wilhelm Koch, Edwin Bremer." Oldenburg : BIS der Universität Oldenburg, 2020. http://d-nb.info/1207469548/34.
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Pozzi, Lu-Ann M. "Macrophages Directly Prime Naïve CD8+ T Cells: a Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/117.
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Professional antigen presenting cells (APCs) represent an important link between the innate and adaptive immune system. Macrophages (MΦs) and dendritic cells (DCs) serve as sentinels in the periphery collecting samples from their environment and processing this information. These cells then present antigenic fragments to T cells in the context of self-MHC molecules. Although a clear role for both of these APCs in the stimulation of already activated or memory T cells has been established, the ability of MΦs to activate naive T cells is still unknown. In this thesis the ability of bone marrow-derived MΦs and DCs to prime naive CD8+ and CD4+ T cells was investigated. Using adoptively transferred transgenic CFSE-Iabeled P-14 T cells, specific for gp33 from lymphocytic choriomeningitis virus in the context of Db, we were able to demonstrate the ability of both MΦs and DCs to induce naive CD8+ T cells proliferation. Once primed by MΦs these T cells gained effector function as shown by interferon- γ (IFN-γ) production and in vivo cytolysis. In addition, immunization of wild type animals with gp33-pulsed MΦs, as well as DCs, led to greater than a 95% reduction in lymphocytic choriomeningitis virus titers. To rule out the role of cross-presentation in the observed priming, two models were used. In the first model, lethally irradiated F1 bxs chimeras reconstituted with either H-2s or H-2b bone marrow were used as host for the adoptive transfer experiments. Since the gp33 peptide binds to Db, the H-2s reconstituted animals should be unable to cross-present the peptide to the P-14 T cells. Using this model, we were able to clearly demonstrate the ability of MΦs to activate naive P-14 T cells to undergo division. Additional experiments, demonstrated that these MΦ primed T cells went on to develop into effector cells. Finally, the ability of the MΦ primed T cells to develop into functional memory cells was demonstrated. To confirm the chimera results, these experiments were repeated using β2 microglobulin deficient animals (whose cells don't express MHC I) as host in adoptive experiments. MΦs were able to stimulate the naive P-14 T cells to divide and gain effector function as demonstrated by the ability to produce IFN-γ. In contrast to the CD8 system, MΦ were poor stimulators of D011.10 CD4+ T cell proliferation. Additionally, D011.10 T cells stimulated by DCs were able to produce interleukin-2 (IL-2), IL-4, tumor necrosis factor and granulocyte-macrophage colony stimulating factor where as MΦ stimulated D011.10 T cells were only able to produce IL-2. In conclusion this body of work clearly demonstrates the in vivo ability of MΦ to stimulate CD8+ T cell proliferation, effector function, as well as the formation of functional CD8+ T cell memory. Whether or not the nature of the memory pools stimulated by the two APCs is exactly the same is still unknown and needs further investigation. The ability of APCs other than DCs to stimulate functional protective memory needs to be considered in the quest to design vaccines that offer broad-spectrum protection.
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Chen, Hong. "Activation and Role of Memory CD8 T Cells in Heterologous Antiviral Immunity and Immunopathology in the Lung: A Dissertation." eScholarship@UMMS, 2002. https://escholarship.umassmed.edu/gsbs_diss/188.
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Each individual experiences many sequential infections throughout the lifetime. An increasing body of work indicates that prior exposure to unrelated pathogens can greatly alter the disease course during a later infection. This can be a consequence of a phenomenon known as heterologous immunity. Most viruses invade the host through the mucosa of a variety of organs and tissues. Using the intranasal mucosal route of infection, the thesis focused on studying modulation of lymphocytic choriomeningitis virus (LCMV)-specific memory CD8 T cells upon respiratory vaccinia virus (VV) infection and the role of these memory CD8 T cells in heterologous immunity against VV and altered immunopathology in the lung.
The VV infection had a profound impact on memory T cells specific for LCMV. The impact included the up-regulation of CD69 expression on LCMV-specific CD8 memory T cells and the activation of their in vivoIFN-γ production and cytotoxic function. Some of these antigen-specific memory T cells selectively expanded in number, resulting in modulation of the original LCMV-specific T cell repertoire. In addition, there was a selective organ-dependent redistribution of these LCMV-specific memory T cell populations in secondary lymphoid tissue (the mediastinal lymph node and spleen) and the non-lymphoid peripheral (the lung) organs. The presence of these LCMV-specific memory T cells correlated with IFN-γ-dependent enhanced VV clearance, decreased mortality and marked changes in lung immunopathology. Thus, the participation of pre-existing memory T cells specific for unrelated agents can alter the dynamics of mucosal immunity. This is associated with an altered disease course in response to a pathogen.
The roles for T cell cross-reactivity and cytokines in the modulation of memory CD8 T cells during heterologous memory CD8 T cell-mediated immunity and immunopathology were investigated. Upon VV challenge, there were preferential expansions of several LCMV-specific memory CD8 T cell populations. This selectivity suggested that cross-reactive responses played a role in this expansion. Moreover, a VV peptide, partially homologous to LCMV NP 205, stimulated LCMV-NP205 specific CD8 T cells, suggesting that NP205 may be a cross-reactive epitope. Poly I:C treatment of LCMV-immune mice resulted in a transient increase but no repertoire alteration of LCMV-epitope-specific CD8 T cells. These T cells did not produce IFN-γ in vivo. These results imply that poly I:C, presumably through its induced cytokines, was assisting in initial recruitment of LCMV-specific memory CD8 T cells in a nonspecific manner. VV challenge of LCMV-immune IL-12KO mice resulted in activation and slightly decreased accumulation of LCMV-specific CD8 T cells. Moreover, there was a dramatic reduction of in vivoIFN-γ production by LCMV-specific IL-12KO CD8 T cells in the lung. I interpreted this to mean that IL-12 was important to augment IFN-γ production by memory CD8 T cells upon TCR engagement by antigens and to induce further accumulation of activated memory CD8 T cells during the heterologous viral infection.
This thesis also systematically examined what effect the sequence of two heterologous virus challenges had on viral clearance, early cytokine profiles and immunopathology in the lung after infecting mice immune to one virus with another unrelated viruses. Four unrelated viruses, [LCMV, VV, influenza A virus or murine cytomegalovirus (MCMV)], were used. There were many common changes observed in the acute response to VV as a consequence of prior immunity to any of three viruses, LCMV, MCMV or influenza A virus. These included the enhanced clearance of VV in the lung, associated with enhanced TH1 type responses with increased IFN-γ and suppressed pro-inflammatory responses. However, immunity to the three different viruses resulted in unique pathologies in the VV-infected lungs, but with one common feature, the substitution of lymphocytic and chronic mononuclear infiltrates for the usual acute polymorphonuclear response seen in non-immune mice. Immunity to influenza A virus appeared to influence the outcome of subsequent acute infections with any of the three viruses, VV, LCMV and MCMV. Most notably, influenza A virus-immunity protected against VV but it actually enhanced LCMV and MCMV titers. This enhanced MCMV replication was associated with enhanced TH1 type response and pro-inflammatory cytokine responses. Immunity to influenza A virus appeared to dramatically enhance the mild lymphocytic and chronic mononuclear response usually observed during acute infection with either LCMV or MCMV in non-immune mice, but LCMV infection and MCM infection of influenza A virus-immune mice each had its own unique features. Thus, the specific sequence of virus infections controls the outcome of disease.
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Tupin, Emmanuel. "Immunomodulation of atherosclerosis : impact of Th balance and CD1d-restricted NKT cells." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-128-8/.
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Hu, Jian. "L'etude de la regulation de l'activation de clones de lymphocytes t humains helpers et cytotoxiques par les molecules cd2." Paris 7, 1988. http://www.theses.fr/1988PA077078.
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Mossalayi, Mohammad. "Caractérisation des précurseurs sanguins et médullaires des lymphocytes T humains : leur purification et les conditions in-vitro requises pour leur différenciation." Poitiers, 1988. http://www.theses.fr/1988POIT2015.
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Miloro, Giorgia. "Déterminer le rôle du récepteur de mort Fas/CD95 dans la co-stimulation des cellules T." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6036.
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Fas (CD95 / TNFRSF6), un récepteur transmembranaire de type I de la superfamille des récepteurs au TNF (TNFR), est un activateur de mort cellulaire bien connu. Cependant, il a également été impliqué dans des fonctions de non-mort cellulaires, telles que la survie, la différenciation et la migration. Alors que la cascade moléculaire qui initie l'apoptose lors de l'engagement de Fas avec son ligand FasL est particulièrement bien décrite, les informations concernant les mécanismes moléculaires sous-tendants les voies non apoptotiques médiées par Fas sont rares.Comme indiqué par les manifestations d’auto-immunité et de lymphoprolifération chez les patients ALPS porteurs de mutations dans le récepteur ou dans son ligand, le système Fas / FasL joue un rôle majeur dans l'homéostasie des lymphocytes T et dans le contrôle de l'auto-immunité et du cancer. D'un côté, la mort médiée par Fas a été décrite comme critique pour (i) la suppression des lymphocytes autoréactifs, et donc dans le maintien de la tolérance périphérique; (ii) le contrôle du nombre de lymphocytes activés par des antigènes faibles lors d'infections par des pathogènes.De l'autre côté, certaines fonctions de non mort de Fas ont été décrites dans les cellules T, parmi lesquelles le rôle de Fas comme récepteur co-régulateur de l’activation du TCR. Malgré l'importance potentielle de ce rôle dans les stratégies immunothérapeutiques, seules quelques études controversées liées à cette implication ont été réalisées. En effet, alors que plusieurs études ont décrit Fas comme un récepteur costimulateur du TCR, d'autres ont défini une inhibition de l'activation des lymphocytes T lors d’une stimulation concomitante de Fas et du TCR. Dans ce contexte, l'objectif de mon projet de thèse consistait à disséquer moléculairement la co-signalisation Fas-TCR.En utilisant à la fois des cellules T primaires et des lignées cellulaires portant un TCR transgéniquespécifique, nous avons pu définir Fas comme un récepteur co-stimulateur. En exploitant les approches biochimiques ainsi que la cytométrie en flux et la microscopie, nous avons déchiffré la co-stimulation Fas-TCR à la fois au niveau fonctionnel et moléculaire. Premièrement, nous avons montré que la co-stimulation Fas-TCR se produit à la fois dans les cellules T naïves et les cellules T mémoire ainsi que dans les souspopulations CD4 + et CD8 +. Moléculairement, nous avons décrit que Fas renforce la signalisation TCR dès les étapes précoces, puisque la phosphorylation des premières protéines impliquées dans l'activation du TCR est augmentée. En outre, les formes membranaires et solubles de FasL sont capables d'initier le signal co-stimulateur de Fas. Enfin, nous avons pu exclure l'implication de FADD et Caspase-8, premiers acteurs de la signalisation Fas, dans la co-activation, et , de manière importante, l'implication du domaine de mort de Fas, suggérant le rôle d'un autre domaine de Fas . Décrire les mécanismes moléculaires et le contexte dans lequel la co-stimulation Fas-TCR se produit pourrait être d'une importance cruciale dans la compréhension de la physiopathologie de Fas dans les cellules T, mais également pour l’établissement de futures stratégies immunothérapeutiquesFas (CD95/TNFRSF6), a type-I transmembrane receptor of the tumor necrosis factor receptor (TNFR) superfamily, is a well-known cell death activator. However, it has been also implicated in non-cell death processes including cell survival, differentiation, migration. Whereas the molecular cascade that initiates apoptosis upon Fas engagement with its ligand FasL is particularly well described, the informations concerning the molecular mechanisms underlying the Fas mediated non-apoptotic pathways are sparse.As indicated by the induction of autoimmunity and lymphoproliferation in ALPS patients harboringmutations in either the receptor or its ligand, the Fas/FasL system plays a major role in T cell immune homeostasis and thus, in the control of autoimmunity and cancer. On one side, the Fas mediated death has been described critical for (i) the deletion of autoreactive lymphocytes, and thus in the maintenance of peripheral tolerance; (ii) the control of the number of lymphocytes activated by weak antigens during pathogen infections.On the other side, and beyond cell death induction, some Fas non-death pathways have been described in T cells, among which the role of Fas as co-regulatory receptor for the TCR during its activation. Despite the potential importance of this role in immunotherapeutic strategies, only few and controversial studies related to this involvement were done. Indeed, whereas several studies have described Fas as a TCR co-stimulatory receptor, others defined an inhibition of T cell activation by Fas-TCR concomitant stimulation. In this context, the aim of my PhD project consisted into molecularly dissect the Fas-TCR co-signaling.By using both primary T cells and cell lines bearing a specific transgenic TCR, we could define Fas as a costimulatory receptor. By exploiting biochemical approaches as well as flow cytometry and microscopy we could decipher the Fas-TCR crosstalk both at functional and molecular level. First, we show that Fas-TCR costimulation occurs in both naïve and in memory T cells as well as in both CD4+ and CD8+ T cell subpopulations.Molecularly, we could describe that Fas enhances the TCR signaling at membrane proximal level, since the phosphorylation of the first proteins involved in TCR activation is increased. Furthermore, both membrane-bound and soluble FasL are capable to initiate Fas co-stimulatory signal. Lastly, we could exclude the involvement of FADD and Caspase-8, first actors of Fas signaling, in the co-activation, and even more importantly, the involvement of the death domain of Fas cytoplasmic tail, unveiling the implication of another Fas receptor domain. To describe the molecular mechanisms and the context where Fas-TCR co-stimulation occurs might be of an outstanding importance in the comprehension of Fas physiopathology in T cells and for future studies that might involve its potential for immunotherapeutic strategies
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Johnson, Deborah K. "The Effects of Immune Regulation and Dysregulation: Helper T Cell Receptor Affinity, Systemic Lupus Erythematosus and Cancer Risk, and Vaccine Hesitancy." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/9199.
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Helper T cells direct the immunological response to foreign pathogens and cancer. To become activated, helper T cells must recognize unique peptides presented on major histocompatibility complex II (pMHCII) by antigen presenting cells (APCs) with their T cell receptor (TCR). While much is known about helper T cell activation signaling cascades and the subsequent roles of helper T cell subsets, the initiation of helper T cell activation by the TCR and other co-receptors is less well understood. Specifically, the affinity of the TCR for its pMHCII can change helper T cell subset fate, proliferation, and alter the risk for activation induced cell death. High affinity TCRs are attractive targets for immunotherapies, but little is known about how helper T cells respond to high affinity TCRs. Here we describe high affinity TCR activation thresholds for both full length TCRs and chimeric antigen receptor TCRs both with and without the presence of the coreceptor CD4 and propose a mechanism whereby CD4 inhibits T cell activation via Lck sequestration and a CD4-independent method. Dysregulated helper T cells play critical roles in the development and perpetuation of systemic lupus erythematosus (SLE), a systemic autoimmune disease that causes widespread inflammation and organ damage throughout the body. Chronic inflammation in SLE affects the immune response to viruses and the risk of developing cancer. However, in SLE patients, it is unclear if viruses initiate the development of cancer directly or if the effects are non-interacting and concomitant. Here we describe the interactions between SLE, viruses, and cancer risk revealing that viruses and SLE do interact to increase the both the overall cancer risk and the risk for hematological malignancies. Due to vaccine efficacy, vaccine preventable diseases (VPDs) are no longer commonly experienced or understood by the public. Vaccines are a victim of their own success and according to the World Health Organization (WHO), vaccine hesitancy (VH) is one of the top threats to global health. VH is the refusal to accept vaccinations and the reasons for VH vary across time, place, and vaccine. Refuting VH is difficult as directly confronting false assumptions can cause individuals to become more entrenched in their position resulting in confirmation bias. Adults with VH attitudes are often motivated by concerns over personal liberty, harm, independence, and body purity. Here we describe the results of a VPD interview- and education-based intervention geared towards promoting positive vaccine attitudes for young adults and demonstrate that education focused on VPDs is more effective than vaccine safety.
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Ali, Qasim. "Contribution to the mathematical modeling of immune response." Phd thesis, Ecole Nationale Supérieure des Mines de Saint-Etienne, 2013. http://tel.archives-ouvertes.fr/tel-00905603.
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The early steps of activation are crucial in deciding the fate of T-cells leading to the proliferation. These steps strongly depend on the initial conditions, especially the avidity of the T-cell receptor for the specific ligand and the concentration of this ligand. The recognition induces a rapid decrease of membrane TCR-CD3 complexes inside the T-cell, then the up-regulation of CD25 and then CD25-IL2 binding which down-regulates into the T-cell. This process can be monitored by flow cytometry technique. We propose several models based on the level of complexity by using population balance modeling technique to study the dynamics of T-cells population density during the activation process. These models provide us a relation between the population of T-cells with their intracellular and extracellular components. Moreover, the hypotheses are proposed for the activation process of daughter T-cells after proliferation. The corresponding population balance equations (PBEs) include reaction term (i.e. assimilated as growth term) and activation term (i.e. assimilated as nucleation term). Further the PBEs are solved by newly developed method that is validated against analytical method wherever possible and various approximate techniques available in the literature.
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Ghenassia, Alexandre. "Induction de réponses mémoires lymphocytaires T CD8 et protection vaccinale après transfert de gènes par le vecteur AAV recombinant." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T032/document.
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La mémoire immunologique est le mécanisme biologique fondamental à la base du développement de la vaccination. La compréhension de ce mécanisme ainsi que de ses interactions avec les différents acteurs du système immunitaire a permis l’élaboration de vaccins qui sont aujourd’hui les garants d’une protection accrue face à l’émergence de maladies infectieuses potentiellement mortelles. La voie d’injection et le mode de transfert de ces vaccins sont des paramètres majeurs à prendre en considération car ils définissent une modulation des réponses immunitaires et de leurs spécificités d’action. De nos jours, seule la voie intramusculaire demeure la voie majoritaire d’administration de vaccins lors de la prophylaxie primaire en santé humaine. Au cours de notre étude, nous nous sommes intéressés à comparer l’injection d’un antigène (l’ovalbumine) selon deux voies d’administration : la voie intramusculaire et la voie intradermique. Nous nous sommes également appuyés sur une technologie du laboratoire qui consiste à transférer des gènes par des vecteurs AAV2/1 recombinants. Nous disposions de deux constructions de ces vecteurs ayant une spécificité pour cibler les cellules musculaires et permettant l’apport d’un effet auxiliaire par les lymphocytes T CD4+ lors d’injections dans des souris femelles. De plus, une de ces constructions nous permettait d’éviter la voie de présentation directe de l’antigène par les cellules dendritiques (DCs) aux lymphocytes T CD8+. Les capacités modulatrices de ces vecteurs nous permirent de montrer pour la première fois que le vecteur AAV2/1 recombinant était capable de faire exprimer un transgène au sein de la peau et d’y générer une réponse cellulaire forte. Nous avons également montré qu’il existait une synergie d’action entre l’effet auxiliaire et la voie intradermique qui améliorait considérablement les réponses cellulaires issues de la présentation croisée d’antigène. Enfin, nous avons pu démontrer que les lymphocytes T CD8+ générés suite à cette synergie d’action présentaient un profil phénotypique de cellules mémoires polyfonctionnelles et capables de protéger l’hôte face à un challenge pathogéniqueImmunological memory is the fundamental biological mechanism at the beginning of the development of vaccination. Understanding this mechanism and its interactions with the various players of the immune system has allowed the development of vaccines that are today the most effective barrier against the emergence of life-threatening infectious diseases. Route of injection and the nature of carriers of these vaccines are key parameters to be taken into consideration because they define a modulation of immune responses and their specific features. Nowadays, only the intramuscular injection route remains the major route of vaccines injection in the context of primary prophylaxis in human health. During our study, we were interested in comparing the injection of antigen (ovalbumin) following two routes of administration: intramuscular and intradermal routes. We also relied on a technology in the laboratory that involves the transfer of genes by rAAV2/1 vectors. We had two constructs of these vectors having specificity to target skeletal muscle cells and allowing us to provide a helper effect from CD4+ T cells during injections into female mice recipients. Moreover, one of these constructs enabled us to avoid the direct presentation of antigens by dendritic cells (DCs) to CD8+ T cells. The capacity of modulation of these vectors allowed us to show for the first time that the rAAV2/1 vector was able to trigger the expression of a transgene in the skin, and there to generate a strong cellular response. We have also shown that CD4+ T cell help and the intradermal route of immunization synergize to improve greatly cellular responses from the cross-presentation of antigens. Finally, we have demonstrated that CD8+ T cells generated following this synergism exhibited a phenotypic profile of polyfunctional memory cells and able to protect the host against a pathogenic challenge
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Benyamine, Audrey. "Ciblage de BTN3A en immunothérapie anti-tumorale basée sur les lymphocytes T Vγ9Vδ2 : Application aux Leucémies aiguës Myéloïdes et au cancer du pancréas." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5007.
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La sous-famille BTN3A comprend 3 isoformes : BTN3A1, A2 et A3. Le domaine intracellulaire B30.2 de BTN3A1 est impliqué dans la reconnaissance du Phosphoantigène (Pag) et l’activation des lymphocytes T Vγ9Vδ2(LTVγ9Vδ2). BTN3A2, dépourvue de B30.2, pourrait être un récepteur-leurre. L’anticorps monoclonal (Acm) 20.1 reconnaît les trois isoformes de BTN3A et sensibilise les tumeurs à la lyse par les LTVγ9Vδ2, mimant l’action des Biphosphonates (N-BP). Nous avons étudié l’expression, la régulation et le ciblage de BTN3A en contexte d’hémopathie maligne et de tumeur solide. Nous avons montré que BTN3A2 est l’isoforme majoritairement exprimée par les blastes de Leucémie Aiguë Myéloïde (LAM) primaire. Cependant, l’Acm 20.1 sensibilise les blastes de LAM primaire à la lyse par les LT Vγ9Vδ2, même ceux résistants aux N-BP. Cet effet est confirmé dans des souris NOD-SCID-γcKO xénogreffées avec la lignée U937 ou des blastes primaires. Nous avons ensuite montré l’expression de BTN3A sur des lignées et des tumeurs pancréatiques primaires et observé qu’elle est associée au pronostic chez les patients atteints de cancer du pancréas. L’expression de BTN3A2, isoforme majoritairement exprimée augmente en contexte de stress cellulaire hypoxique et métabolique. La faible expression de BTN3A1 comparativement à BTN3A2 et le clivage des BTN3A pourraient favoriser l’échappement tumoral à la reconnaissance par les LT Vγ9Vδ2. Cependant, les LT Vγ9Vδ2 ont des fonctions cytolytiques préservées en hypoxie. Le ciblage de BTN3A par l’Acm 20.1 sur les tumeurs étudiées, en restaurant la lyse par les LT Vγ9Vδ2, offrirait des perspectives thérapeutiques notamment pour les tumeurs chimiorésistantesBTN3A subfamily comprises three isoforms: BTN3A1, A2 and A3. The B30.2 intracellular domain of BTN3A1is involved in Phosphoantigen recognition and Vγ9Vδ2 T cells activation. BTN3A2, devoid of B30.2 domain, could be « a decoy receptor ». The agonist anti-BTN3A monoclonal Antibody (mAb) 20.1 recognizes the three BTN3A isoforms and sensitizes tumors to Vγ9Vδ2 T cell lysis. This mAb mimics the effect of Aminobisphosphonates (N-BP). We studied BTN3A expression, regulation and targeting in tumors of hematological and solid origin. We showed that primary Acute Myeloïd Leukemia (AML) blasts express BTN3A with a main expression of BTN3A2. However, the 20.1 mAb sensitizes primary AML blasts to Vγ9Vδ2 T cell lysis even N-BP-poorly sensitive blasts. This was confirmed in NOD-SCID-γc KO mice xenografted with U937 human cell line or primary blasts. Next, we have demonstrated BTN3A expression in pancreatic cell lines and primary tumors. We observed that BTN3A is associated to prognosis in patients with pancreatic cancer. BTN3A2 is the most highly expressed isoform and its level of expression increases upon hypoxic and metabolic cellular stress. The weak expression of BTN3A1 compared to BTN3A2 isoform together with BTN3A molecules shedding could constitute an immune escape mechanism of tumor cells from Vγ9Vδ2 T cells recognition. Though, Vγ9Vδ2 T cells have preserved cytotoxic functions under hypoxic condition. BTN3A targeting with anti-BTN3A 20.1 mAb on the tumors we studied would open new therapeutic perspectives notably in chemoresistant tumors, thanks to the restoration of Vγ9Vδ2 T cell lysis
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Schirmacher, Anastasiya. "Modification of transmembrane peptides to probe SNARE-induced membrane fusion and cross-presentation of membrane-buried epitopes." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-1576-F.
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Hélie, Pauline. "Rôle de l'activateur tissulaire du plasminogène dans la réponse immunitaire au cours de l'encéphalomyélite auto-immune expérimentale." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMC409.
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L’activateur tissulaire du plasminogène (tPA) est une sérine protéase qui est synthétisée principalementpar les cellules endothéliales des vaisseaux. Initialement découvert dans le compartiment vasculaire où sa fonctionprincipale est de participer à la fibrinolyse, le tPA est aussi exprimé dans le parenchyme cérébral par plusieurstypes cellulaires comme les neurones ou les oligodendrocytes. Le tPA est impliqué dans de nombreuses fonctionscérébrales comme la plasticité synaptique ou encore la potentialisation glutamatergique. Le tPA est aussi un acteurclé de la neuroinflammation. Il active la microglie et participe à l’ouverture de la barrière hémato-encéphalique pardes effets de type cytokine et via son domaine protéase en générant de la plasmine à partir du plasminogène. Uneactivité plus importante du tPA est retrouvée dans le liquide céphalorachidien des patients atteints de sclérose enplaques (SEP). De plus, le tPA possède des aspects délétères dans son modèle murin, l’encéphalomyélite autoimmune expérimentale (EAE). Dans le but de mieux comprendre le rôle du tPA dans la physiopathologie de l’EAE,nous nous sommes intéressés à son implication dans la réponse immunitaire pendant la maladie. Nos donnéesmontrent que les animaux tPA-/- ont des scores cliniques moins importants que les animaux WT pendant une EAE.Les nombres absolus de LT CD4+, de microglie activée et de macrophages infiltrés, ainsi que de cellulesdendritiques sont moins importants dans le parenchyme spinal des animaux tPA-/- en comparaison avec lesanimaux WT. En lien avec ces observations in vivo, le tPA augmente in vitro l’activation et la prolifération des LTainsi que la sécrétion d’IL-6 par un mécanisme dépendant du domaine protéase et de la génération de plasmine.Dans des expériences in vitro en collaboration avec l’équipe du Dr Diego Clemente, le tPA induit l’augmentation del’expression des molécules du CMH de classe II et des molécules de costimulation à la surface des cellulesdendritiques et des macrophages par un effet de type cytokine, suggérant une capacité plus importante pour cescellules à présenter des antigènes en présence de tPA. Notre étude apporte une meilleure compréhension du rôledu tPA dans la réponse immunitaire pendant l’EAE et ouvre de nouvelles perspectives dans l’étude de l’axe tPA/plasmine dans la physiopathologie de la maladieTissue plasminogen activator (tPA) is a serine protease, mainly synthesized by endothelial cells of vessels.Initially discovered in the vascular compartment where its main function is to participate to fibrinolysis, tPA is alsopresent in the cerebral parenchyma, and expressed by several cell types like neurons or oligodendrocytes. tPA isinvolved in many physiological brain functions such as synaptic plasticity or glutamatergic potentiation. tPA is alsoa main actor of neuroinflammation. It activates microglia and participates in the opening of the blood-brain barrier(BBB) by cytokine-like effects and via its protease domain and plasmin generation from plasminogen. Interestingly,tPA activity is more important in cerebrospinal fluid of multiple sclerosis (MS) patients. In addition, tPA revealsdeleterious aspects in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. In order tobetter understand the role of tPA in EAE physiopathology, we focused on its involvement in the immune responseduring disease. tPA-/- EAE animals present less severe clinical scores than WT animals. Our results indicate alsothat absolute numbers of CD4 + T cells, activated microglia and infiltrated macrophages, as well as dendritic cellsare less important in the spinal parenchyma of tPA-/-. In connection with these in vivo observations, our in vitro datashow that tPA increases activation and proliferation of T cells, as well as IL-6 secretion by a protease-dependentmechanism and plasmin generation. In experiments in collaboration with Dr Diego Clemente's team, our data showthat tPA increases the expression of MHC class II and costimulatory molecules on the surface of dendritic cells andmacrophages in vitro by a cytokine-like effect, suggesting a more important ability for these cells to present antigenswith tPA. Our study provides a better understanding of the role of tPA in immune response during EAE, and opensup new perspectives in the study of the tPA / plasmin axis in the physiopathology of the disease
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Wang, Fei. "WC1 mediates T cell activation and is required for the response of bovine γδ T cells to Leptospira antigen." 2009. https://scholarworks.umass.edu/dissertations/AAI3349748.
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Workshop cluster 1 (WC1) molecules are exclusively expressed on the surface of γδ T cells. They belong to the scavenger receptor cysteine-rich (SRCR) superfamily and are encoded by a multiple-gene family. WC1 molecules are divided into three major groups, WC1.1, WC1.2 and WC1.3, on the basis of antibody reactivity. The expression of WC1 molecules from these groups correlates with differences in γδ T cell responses. Particularly, the expression of receptors within the serologically-defined WC1.1 group correlates with the capacity to respond to Leptospira antigen. The potential role of WC1 as a co-stimulatory molecule for the γδ TCR is suggested by the presence of several tyrosine-based motifs in their intracellular domains. In this study, we found that WC1 was constitutively phosphorylated in ex vivo bovine γδ T cells and associated with src family tyrosine kinases. Crosslinking of WC1 molecules resulted in an increase in WC1 phosphorylation and co-crosslinking of WC1 and γδ TCR together prolonged WC1 phosphorylation. We identified the second tyrosine residue on the WC1 intracellular tail as the primary phosphorylation target in WC1.1 and WC1.2 intracellular sequences in both in vitro and in vivo assays. And phosphorylation of the second tyrosine was required for the WC1-mediated potentiation of TCR-induced T cell proliferation, suggesting that WC1 acts as a co-stimulatory molecule for γδ TCR. The cytoplasmic tails of WC1.1 and WC1.2 were also phosphorylated on serine and PKC activity was required for phosphorylation-dependent endocytosis of WC1.1 or WC1.2. Finally, we used RNA interference to directly investigate the role of WC1 expression in the response to Leptospira borgpeterseneii . We found that when a subset of WC1 transcripts were down-regulated by RNA interference, the proliferation of cells in response to Leptospira antigen and the production of IFN-γ was significantly reduced. Our data directly demonstrate that the co-receptors in the WC1 family act as an essential component for Leptospira recognition and/or activation of γδ T cells.