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1
Pido, Jeffrey. "Factors affecting thymic-dependent T cell reconstitution." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406587.
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Cobb, Dustin. "T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/372.
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The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection.
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Long, Tianying. "Autoaggressive T cells in insulin-dependent diabetes mellitus." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60429.
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Considerable evidence suggests that insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated autoimmune process that is directed against antigenic target(s) on pancreatic $ beta$ cells. To better understand T cell involvement in the pathogenesis of IDDM, a panel of T cell hybridomas were produced from pancreas-derived T cells of spontaneously diabetic NOD mice. A total of 119 hybridomas were constructed from 8 fusions and 94 of these were tested. Twelve hybridomas were found to be islet-reactive since they produced high level of interleukin-2 (IL-2) in the presence of NOD islet cells and NOD antigen-presenting cells (APC's). The responses could also be detected against islet cells of other strains (i.e. C3H/Hej or C57B1/6), but only in the presence of the NOD APC's. Phenotyping of these islet-reactive hybridomas showed that all of them were CD3$ sp{+}$CD4$ sp{+}$. Furthermore, a high frequency (39%) of CD4$ sp{+}$ T hybridomas in the panel were found to be islet reactive. In addition, analysis of T-cell receptor (TCR) V$ sb{ beta}$ expression of these islet-reactive T-cell hybridomas revealed that TCR V$ sb{ beta}$ element usage is heterogeneous unlike findings in some experimentally induced autoimmune diseases.
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Zarozinski, Christopher C. "T Cell Receptor-Dependent and Independent Events During Potent Anti-Viral T Cell Responses." eScholarship@UMMS, 1998. http://escholarship.umassmed.edu/gsbs_diss/175.
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The relative contribution of T cell receptor-dependent stimulation versus TcR-independent bystander stimulation in the massive increase in the number of activated proliferating CD8+ T cells seen during acute many acute viral infections is unclear. To determine if this increase was the result of TcR-independent bystander activation and proliferation, anti-viral cytotoxic T lymphocytes were induced in vivo via DNA immunization so that the anti-viral immune response could be examined in the absence of the high levels of cytokines generated during acute infection. After a single immunization with a plasmid encoding the nucleoprotein of the lymphocytic choriomeningitis virus (LCMV) a nearly 2 log10 reduction in viral titers in the spleen was observed 3 days after LCMV infection. After 2 or 3 immunizations a greater that 3 log10 inhibition of viral titers in the spleen was observed, with most animals having no detectable virus. After intracerebral challenge vaccinated animals displayed either protection or enhanced immunopathology leading to accelerated kinetics of death. By limiting dilution analysis LCMV-specific CTL precursors were detected in both the spleen and lymph nodes of vaccinated animals. C57BL/6 mice inoculated with DNA demonstrated an anamnestic CTL response detectable at days 4 after LCMV challenge. However, the numbers of CTL precursors elicited by DNA vaccination was too low to determine if cytokine-mediated TcR-independent bystander activation and proliferation had taken place.
HY-specific TcR-transgenic mice, which have a restricted TcR repertoire, and LCMV-carrier mice, which are tolerant to LCMV, were used to determine the extent of TcR-independent bystander activation and proliferation during acute LCMV infection. LCMV infection of C57BL/6 mice induced CTL that lysed uninfected H-2k and H-2d allogeneic targets, but, LCMV-induced CTL from HY- transgenic mice lysed only the H-2k-expressing cells. The HY-mice generated both anti-H-2k and anti-H-2d CTL in mixed lymphocyte cultures, strongly suggesting that the generation of allospecific CTL during acute LCMV-infection is antigen specific. During the LCMV infection there was blastogenesis of the CDB+ T cell population, but the HY-specific T cells remained small in size, and did not alter their expression of the activation molecules CD44 and MEL-14. In order to examine the potential for bystander stimulation under conditions of a very strong CTL response, T cell chimeras were made between normal and HY-transgenic mice. Even in the context of a normal vicus-induced CTL response, no stimulation of HY -specific T cells was observed, and HY-specific cells were diluted in number by day 9 post-infection. In LCMV-carrier mice in which donor and host T cells could be distinguished by Thy 1 allotypic markers, adoptive transfer of LCMV-immune T cells into LCMV-carrier mice, whose T cells were tolerant to LCMV, resulted in activation and proliferation of donor CDB cells but little or no activation of host CDB+ T cells. These results show that TcR-independent bystander activation of non virus-specific T cells is not a significant component of an anti-viral T cell response and support the hypothesis that the massive polyclonal CTL response to LCMV infection is virus-specific.
T cells activated during potent anti-viral immune responses are sensitized to undergo apoptosis after strong TcR-stimulation in a process known as activation-induced cell death (AICD). To determine if T cells, not participating in the immune response were also subject to AICD, LCMV-carrier mice were used. Using TUNEL flow cytometry, it was shown that after reconstitution of Thy 1.2+ LCMV-carrier mice with spleen cells from Thy 1.1+ LCMV-immune mice, the Thy 1.2+ host T cells which were not specific for the virus and did not proliferate in a bystander fashion, were rendered sensitive to TcR-induced apoptosis in vitro. This bystander sensitization to AICD was shown not to be dependent on the continued presence of activated proliferating donor cells during the in vitro culture period. Bystander sensitization to AICD was not the result of an antigen presenting cell defect, but rather was the result of an in vivo conditioning of the T cells themselves. The mechanism of this sensitization was, at least, partially dependent on the ability of host T cells to respond to IFNγ, and on the expression of Fas ligand on the activated, proliferating donor cells. This bystander sensitization to AICD may explain why memory T cell responses are so poor during acute viral infection and can serve as a potential mechanism for virus-induced immunosuppression.
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English, Kieran. "Deciphering the cellular mechanisms promoting CD4+ T cell-dependent intrahepatic CD8+ T cell immunity." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27735.
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The liver is the body’s largest internal organ and assumes many important physiological and metabolic functions. It is also well-established that the liver possesses unique immunological properties and a delicate balance between tolerance and immunity exists within this large organ. CD4 T cell help to CD8 T cells has emerged as a critical factor involved in promoting robust CD8 T cell responses against viral and tumour antigens. Studies in humans and chimpanzees indicate that CD4 T cells are critical for strong intrahepatic CD8 T cell responses and the spontaneous control of hepatitis C virus and hepatitis B virus infections. However, due to limitations of current small animal models, the precise role of CD4 help in orchestrating intrahepatic CD8 T cell responses, and the mechanisms by which CD4 help is transferred to intrahepatic CD8 T cells remains poorly understood. Using an rAAV based approach to express model antigens containing both CD4 and CD8 T cell epitopes specifically in hepatocytes, we first demonstrate that CD4 help enhances the primary expansion of CD8 T cells responding to hepatocyte expressed antigens, which is critical for the generation of a large pool of memory CD8 T cells in the liver, blood and lymphoid tissues. Importantly, we decipher a novel mechanism facilitating the transfer of CD4 help to intrahepatic CD8 T cells: cognate CD40-CD40L licensing of hepatic XCR1 cDC1s in situ within portal tracts and central veins. In deciphering this mechanism, we also uncovered a previously unrecognised interconnected myeloid cell network contained within portal tracts in the steady state and following antigen expression in the liver. Together, these discoveries yield important insights into the mechanisms governing the outcome of intrahepatic immune responses, and suggest avenues for future work, with the possibility of translational research to explore novel therapies to manipulate intrahepatic immunity and hence beneficially alter outcomes in human liver diseases.
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Camoglio, Luisa. "IL-12 and T-lymphocyte dependent mucosal immune responses." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/82609.
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Wang, Shu-Fang. "Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling." 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/137035.
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Macintyre, Andrew Neil. "Phosphoinositide dependent kinase 1 maintains T-Cell metabolism during proliferactive stress." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510626.
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Hertweck, Arnulf. "Dicer-dependent regulation of gene expression and development in T lymphocytes." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501208.
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Martin, Matthew David. "Time-dependent alterations in memory CD8 T cell function after infection." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3138.
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CD8 T cells play a critical role in the clearance of pathogenic bacteria, viruses, and protozoan parasites. Upon encountering their cognate antigen through either infection or vaccination, naïve CD8 T cells undergo robust proliferative expansion, which is followed by contraction and the formation of a memory population. Memory CD8 T cells are long-lived, and because they persist in increased numbers and possess enhanced functional abilities compared to naïve CD8 T cells, they are able to provide the host with increased protection following re-infection. Because of these properties, vaccines designed to elicit memory CD8 T cells have the potential to reduce health care burdens related to infection with pathogens including human immuno deficiency virus (HIV), malaria, influenza, and hepatitis virus. However, stimulating protective CD8 T cell responses against these pathogens through vaccination has proven challenging. Therefore, a better understanding of the properties of memory CD8 T cells generated following vaccination, and the characteristics of memory CD8 T cells best suited for providing protection against diverse pathogens is needed.
While memory CD8 T cells can be maintained for as long as the life of the host, evidence suggests that their properties change with time after infection. Because CD8 T cell-mediated protection is based upon both the numbers and quality or functional abilities of memory cells present at the time of re-infection, changes in memory CD8 T cell function over time could impact their ability to provide protection upon re-infection. Therefore, a better understanding of how memory CD8 T cells change with time after infection is needed. As part of the studies presented in this thesis, I found that the phenotype and function of memory CD8 T cells including localization, interleukin (IL)-2 cytokine production, responsiveness to homeostatic cytokines, metabolic capabilities, and proliferation and secondary memory generation potential change with time after infection. Interestingly functional changes could not be completely explained by changes in subset composition that occur with time, as changes over time were also seen in defined CD62Lhi subsets. Importantly, functional changes of memory CD8 T cells that occurred with time led to an increased ability to provide protection against a chronic viral infection. These data improve our knowledge of the capabilities of memory CD8 T cells generated following infection, and suggests that the outcome of vaccination strategies designed to elicit protective memory CD8 T cells using single or prime-boost immunizations will depend upon the timing between antigen encounters.
Following re-infection, memory CD8 T cells become activated and produce effector cytokines and cytolytic molecules that aid the host in clearing invading microbes. Activation can be triggered not only through cognate antigen recognition, but also by antigen-independent cytokine driven signals. However, our knowledge of how antigen-dependent and –independent signals contribute to CD8 T cell activation and protection following infection is incomplete. In the second part of my thesis, I show that the ability of memory CD8 T cells to become activated in response to inflammation decreases with time after infection, that antigen and inflammation act synergistically to induce activation of memory CD8 T cells, that the presence of cognate antigen enhances activation of memory CD8 T cells that contribute to clearance of infection, and that bystander memory CD8 T cell responses following unrelated bacterial infection do not provide the host with a protective benefit.
Together, the data in this thesis further our understanding of memory CD8 T cells generated following infection and/or vaccination, and the properties of memory CD8 T cells important for providing protection upon re-infection with invading pathogens.
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Doll, Kanne Katherine Lee. "CD8 T cell dependent and independent immunity against Plasmodium following vaccination." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3073.
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Infection with Plasmodium species leads to nearly 400,000 deaths a year despite widespread use of mosquito bed nets, insecticides, and anti-malarial drugs. To date, there is not a licensed vaccine capable of providing complete protection from Plasmodium infection to vaccinees. Whole parasite vaccination of humans and rodents can achieve complete protection in vaccines, but the dose of sporozoites, number of administrations, and production concerns in generating these types of vaccines will likely prevent these approaches from achieving worldwide use. However, the protective immunological responses against Plasmodium parasites engendered by these vaccination approaches can be studied and aid in the development of advanced subunit vaccines against Plasmodium. Using rodent models of malaria to elucidate the features of protective immunity engendered by whole parasite vaccination, it has been repeatedly shown that CD8 T cell responses directed against liver-stage parasite antigens can provide complete protection with some contribution by CD4 T cells and antibody responses depending on the model system studied. However, the quantatitive and qualitative requirements for CD8 T cell immunity against Plasmodium remains largely undefined. To enhance our understanding of how to generate protective immunity against Plasmodium, I have utilized rodent models of malaria to study the superior protection afforded from single-dose vaccination with virulent sporozoites administered under prophylatic chloroquine-cover, referred to as chemoprophylaxis sporozoites (CPS) vaccination, compared to the well-studied approach of administering radiation-attenuated Plasmodium sporozoites (RAS). RAS vaccination has long been considered the “gold standard” in vaccination due the ability of RAS vaccination to engender complete protection following sporozoite challenge of vaccinated humans and rodents. However, CPS vaccination is arguably a superior vaccination approach since it can achieve protection through less vaccine administrations relative to RAS vaccination, but the immunological basis of this enhanced CPS vaccine-induced immune response was unclear. In my study, I utilized a stringent host/parasite model to find that C57Bl/6 mice administered CPS vaccination with P. yoelii sporozoites elicit substantially higher parasite-specific CD8 T cell responses than RAS vaccination, but CPS-induced CD8 T cells were not necessary for protection following liver-stage sporozoite or blood-stage parasite challenge. CPS vaccination resulted in a low grade, transient parasitemia shortly following cessation of chloroquine treatment, which lead to the generation of potent antibody responses to blood-stage parasites; this blood-stage parasite-specific antibody response correlated with sterilizing protection in sporozoite challenged CPS-vaccinated mice. Therefore, my data provide a mechanistic basis for enhanced protective immunity elicited by single-dose CPS vaccination in a rodent model that is independent of CD8 T cells. The other portion of my work examines how CD8 T cell specificity impacts protective capacity against Plasmodium. I show that robust CD8 T cell responses of similar phenotype are mounted following prime-boost immunization against three novel Plasmodium berghei protein-derived epitopes in addition to a previously described protective, immunodominant epitope. I show that only CD8 T cells specific to sporozoite surface-expressed protein-derived epitopes, but not the intracellular protein-derived epitopes, are efficiently recognized by sporozoite-infected hepatocytes in vitro. These results suggest that antigenic targets must be efficiently presented by infected hepatocytes for CD8 T cells to eliminate liver-stage Plasmodium infection and proteins expressed on the surface of sporozoites may be good target antigens for protective CD8 T cells. Collectively, my work highlights the ability to generate protective CD8 T cell independent and dependent immunity against Plasmodium infections, whether achieved through potent blood-stage-specific antibody responses, or via numerically large monospecific CD8 T cell responses that target parasite antigens that are efficiently presented during liver-stage infection. These studies are relevant in understanding how to efficiency engender protective immunity against Plasmodium, and could aid in the advancement of subunit vaccination approaches that generate immunity through the priming of responses from multiple arms of the immune response, targeting both the liver- and blood-stages of Plasmodium.
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Loh, Yik Wen. "Analysis of CD4 T cell-dependent skin and islet graft rejection." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13085.
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Studies described in this thesis made use of the CD4+ 5C.C7 TCR transgenic model to analyse CD4+ T cell responses in two models of fully MHC-mismatched non-vascularised grafting: skin and islet grafts. The crossreactive specificities of the 5C.C7 TCR model allow the investigation of direct allorecognition and the role of heterologously primed memory cells in allogeneic graft rejection or acceptance. Data presented is consistent with a model in which memory, not naïve CD4+ T cells, primed by environmental exposure before the time of grafting and expressing allo-crossreactive specificities, are uniquely capable of initiating graft rejection by entering graft site directly from the bloodstream, attacking the graft and liberating MHC antigens from the graft so that they reach the circulation and can then interact with both naïve and memory cells in the secondary lymphoid tissues. This highlights the critical role of memory cells in initiating allograft rejection and has important implications for future development of tolerance strategies for clinical application. Additionally, work presented includes the establishment of a diabetogenic drug induced diabetes model for islet transplantation, as well as the novel application of intravital multiphoton system to image full thickness flank skin and islet grafts under the kidney capsule.
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Wang, Xiaoting Z. "Organ-Dependent and Epitope-Dependent Repertoire Usage and Apoptosis of Antigen-Specific T Cells in Viral Infections: a Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/285.
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During virus infections, activation of CD8 T cells takes place in secondary lymphoid organs including spleen and lymph nodes. The kinetics of the T cell response in lymphoid tissues has been clearly studied. However, a large number of virus-specific T cells disseminate into various nonlymphoid tissues. As reservoirs for effector and memory cells, nonlymphoid organs play an important role for defending against infections. T cell responses in nonlymphoid organs may differ from lymphoid organs.
T cell repertoire usage in lymphoid and nonlymphoid tissues was studied in an acute lymphocytic choriomeningitis virus (LCMV)-infected murine model. The hierarchy of CD8 T cell specificities was examined with cytotoxic T lymphocyte (CTL) sodium 51 chromate (51Cr) release assays and intracellular interferon (IFN)γ assays. T cell receptor (TCR) repertoire usage was determined by complementarity determining region (CDR)3 length spectratyping analysis. Both T cell specificity and TCR repertoire usage revealed some similarities and differences between several organs. Within an epitope-specific CD8 T cell population, the TCR repertoire usage was similar in different organs of the same mouse, but highly heterogeneous between individual mice with genetically identical backgrounds.
A very restricted CD4 TCR repertoire was observed in BALB/c mice after secondary respiratory syncytial virus (RSV) infection. Most of the CD4 T cells of BALB/c mice pre-immunized with RSV glycoprotein (GP) predominantly express Vβ14 TCR with discrete oligoclonal CDR3 regions. Depletion of Vβ14 CD4 T cells dramatically reduced immunopathology.
The apoptotic phenotype of LCMV-specific CD8 T cells was studied in various lymphoid and nonlymphoid tissues during acute and memory stages of infections. Peripheral tissues (peritoneal cavity (PEC), fat pad, and lung) reacted with a much lower frequency with the early apoptotic marker Annexin V than those in spleen and lymph nodes. This was not due to a TCR-based selection because similar TCR spectratypes were seen in different organs. Activated lymphoid and nonlymphoid T cells from LCMV GP33 transgenic mice, which have identical TCR α and β chains on all T cells, had differential Annexin V binding. When incubated shortly in vitro, most Annexin V+ T cells rapidly fragmented their DNA and became terminal transferase-mediated dUTP nick end-labeling positive (TUNEL+), while much fewer Annexin V- cells became TUNEL+. Therefore, those Annexin-V+ cells were truly in a pre-apoptotic stage. The differential spontaneous apoptosis in different tissues is independent of several death/survival-related molecules, including Fas/Fas ligand (FasL), turner necrosis factor (TNF)α, interleukin (IL-15), perforin, B cell lymphoma (Bcl)-2 and independent of virus tropism.
I further investigated the significance of the high Annexin V reactivity of lymphoid T cells. Pre-apoptotic cells were prevented from fragmenting their DNA by anti-CD3 or IL-2 stimulation in vitro. However, this pre-apoptotic phenotype precluded generation of memory. Annexin V reactive cells did not give rise to long-lived memory after being transferred into naïve hosts. The pre-apoptotic phenotype is also an intrinsic property of the epitope. Different proportions of apoptotic cells were found in LCMV effector and, memory T cells specific to two different epitopes, nucleoprotein (NP)396 and GP33. Higher Annexin V reactivity of NP396-specific CD8 T cells was independent of virus tropism and duration of encounter with antigen. Higher expression of IL-7R was found in peripheral, Annexin V- and GP33-specific CD8 T cells, indicating that IL-7-dependent signals may inhibit apoptosis.
Nonlymphoid T cells were more resistant than lymphoid T cells to activation-induced cell death (AICD). When stimulated with anti-CD3 in vitro for 40 hours (hr), a significantly reduced number of splenic transgenic T cells were recovered with much higher frequency of Annexin V reactivity and TUNEL staining than transgenic T cells from PEC. Consistent with the finding that Fas and FasL regulates AICD, a much lower expression of Fas and FasL was observed in PEC and lung transgenic T cells than spleen and lymph nodes after short time stimulation. FasL blockage largely increased cell-number recovery and reduced Annexin V and TUNEL staining of spleen transgenic T cells.
Interestingly, the leukocyte environment played an important role of deciding the fate of transgenic T cells. When placing activated spleen transgenic T cells with excess infected PEC cells, spleen transgenic cells rapidly reduced their Annexin V staining and TUNEL staining and were recovered with greater number after stimulation. Vice versa, PEC transgenic T cells became Annexin V and TUNEL positive with lower numbers of cells recovered when placed with excess splenocytes. Less detection of Annexin V+ cells in peripheral tissues was not due to rapid phagocytosis by macrophages, because Cytochalasin D, which can inhibit phagocytosis, did not induce equal amount of pre-apoptotic cells in spleen and PEC. This reduced death in the periphery may contribute to the long-term maintenance of nondividing nonlymphoid memory T cells, enabling them to efficiently function without being driven into apoptosis.
Overall, this study characterizes in detail the different T cell repertoire usage and apoptosis of virus-specific T cells based on their organ localization and specificities and helps to better understand T cell immunity after infections and vaccine design.
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Ouyang, Li. "The Blimp-1-Dependent Interleukin-2 Inhibitory Loop in CD4+ T cells." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_theses/98.
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IL-2 has multiple functions in T cell-mediated adaptive immunity. The stringent control of its expression is important for T cell activation, proliferation and the subsequent T cell clone contraction. Our lab has recently shown that the transcriptional repressor Blimp-1 is part of a negative feedback loop which controls IL-2 gene expression in mice. Understanding the molecular mechanisms of this signaling loop in T cells might help us to better understand the regulation as well as the role of IL-2 in T cell immunity. The human ortholog to murine Blimp-1 is termed PRDI-BF1 (each encoded by the respective Prdm1 gene). Both genes contain five zinc finger regions, whereby the first two zinc fingers are dispensable for DNA binding. In case of the human protein they are instead required to recruit the G9?Ñ methyltransferase to the gene promotor. We found that the human wild-type PRDI-BF1 protein suppressed IL-2 production in murine T cells, while deletion of the first two zinc fingers abolished this ability. Thus, a similar Blimp-1-mediated methylation mechanism might exist in IL-2 gene silencing. IL-2/IL-2R signaling is indispensable for Blimp-1 induction. PI-3Kinase and Stat5 are downstream of the IL-2 receptor complex and are known to contribute to IL-2 inhibition in T cells from C57BL/6 mice. However, activating only these two pathways are still not sufficient to induce Blimp-1 or suppress IL-2 expression in in IL-2R beta-/- mice. The Blimp-1-dependent IL-2 self regulatory loop is not functional in IL-2R beta-/-mice. In order to conveniently study this dysregulation we crossed these mice with a GFP transgenic strain in which the GFP transgene is under the control of IL-2 promoter sequence. In IL-2R beta-/-IL-2p-GFP mice about five times as many spleenic CD4+ T cells transcribe IL-2pGFP, compared to the littermate IL-2R beta+/-IL-2p-GFP control animals. And most of the GFP cells demonstrate activated phenotype (CD44HighCD62Llow). Blimp-1 is known as a master regulator of B cell terminal differentiation. Since a recent report indicated that IL-2 signaling via STAT5 constrains Th17 Cell differentiation, we speculated that Blimp-1 might play a similar role in effector T cell differentiation. In order to evaluate this possibility, activated CD4+ T cells from C57BL/6 mice were transduced with Blimp-1 and cultured under Th17 polarizing conditions. Blimp-1 overexpression in did not change the profile of IL-17 production.
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Zheng, Lei. "eIF4E-dependent translational control of gene expression in CD4+ T cell subsets." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114555.
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Regulatory T (Treg) cells are important to maintain immune tolerance and homeostasis. Previous genome-wide transcriptional profiles have defined canonical signatures of Treg cells that distinguish them from effector T (Teff) cells. However, compelling evidence shows that changes in total mRNA levels do not always correlate with the protein levels due to post-transcriptional regulation. Our laboratory recently has performed the first genome-wide study on translational control of gene expression in primary CD4+ T cell subsets, and eukaryotic translation initiation factor 4E (eIF4E) is found to be translationally suppressed in activated Treg cells compared to activated Teff cells. We also showed that differential eIF4E levels in CD4+ T cell subsets correlated with translation of eIF4E-sensitive cell cycle-related mRNAs, and modulated proliferation and Foxp3 expression in activated CD4+ T cells. Thus, CD4+ T cell subsets exhibit specific translational programs that orchestrate expression of genes which play important roles in the regulation of fundamental cellular processes in CD4+ T cells lineage commitment, genetic programming and function. In this study, we hypothesized that differential expression of eIF4E impacts proliferative and cytokine responses in T cells. We first show that shRNA knockdown of eIF4E dramatically reduces CD4+ T cell proliferation and inflammatory cytokine secretion. As eIF4E activity is directly repressed by the eIF4E-binding proteins (4E-BPs), we hypothesized that CD4+ T cell responses may be skewed in 4E-BP1/2 deficient mouse model. Interestingly, 4E-BP1/2 deficient T cells are not enhanced in their proliferative response following activation, and 4E-BP1/2 deficiency does not abrogate the suppressive function of Treg cells. Moreover, Teff cells lacking 4E-BP1/2 are less sensitive to TGF-b-mediated induction of Treg cells, although rapamycin-mediated Treg induction is not abolished. Collectively, our findings demonstrate that eIF4E could regulate some CD4+ T cell responses in a 4E-BPs-dependent or –independent manner. Specific targeting of eIF4E prominently affects the T cell functional properties, which could open a new era for therapeutic treatment of some autoimmune disease.<br>Les cellules régulatrices T (Treg) sont importantes pour la maintenance de la tolérance et de l'homéostasie immunitaires. Des analyses pan-génomiques ont précédemment permis d'établir les signatures transcriptionnelles distinguant les cellules Treg des cellules effectrices T (Teff). Toutefois, de nombreuses études montrent que les changements dans les niveaux d'ARN messager totaux ne correspondent pas toujours avec les niveaux des protéines à cause de la régulation post-transcriptionnelle. Notre laboratoire a récemment effectué la première analyse pan-génomique du contrôle traductionnel de l'expression des gènes dans les sous-populations des cellules T CD4 primaires, montrant que la traduction du facteur d'initiation eucaryote 4E (eIF4E) est réduite dans les cellules Treg activées comparées aux cellules Teff activées. Nous avons également montré que les différents niveaux de eIF4E présents dans les sous-populations des cellules T CD4 corrèlent avec le niveau de traduction des ARN messager régulés par eIF4E relatifs au cycle cellulaire, a la modulation de la prolifération et a l'expression de Foxp3 dans des cellules T CD4 activées. Ainsi, les sous-populations de cellules T CD4 présentent des programmes spécifiques de traduction qui régissent l'expression de gènes qui jouent un rôle important dans la régulation de processus cellulaires fondamentaux pour l'engagement dans une lignée, la programmation génétique et de la fonction des cellules T CD4. Dans cette étude, nous avons émis l'hypothèse que l'expression différentielle d'eIF4E affecte la prolifération et les réponses cytokiniques des les cellules T. Nous montrons d'abord que la répression de eIF4E par shRNA réduit considérablement la prolifération des cellules T CD4 et la sécrétion de cytokines inflammatoires. Comme l'activité d'eIF4E est directement réprimée par les protéines liées à eIF4E (4E-BP), nous avons émis l'hypothèse que les réponses des cellules T CD4 peuvent être affectées dans un modèle de souris déficientes pour 4E-BP1/2. Les cellules T déficientes 4E-BP1/2 ne sont pas rehaussée dans leur réponse proliférative après activation, et la déficience en 4E-BP1/2 n'abroge pas la fonction suppressive des cellules Treg. En outre, les cellules Teff qui n'expriment pas 4E-BP1/2 sont moins sensibles à l'induction de cellules Treg médiée par le TGF-b, alors que l'induction médiée par la rapamycine n'est pas abolit. Collectivement, nos résultats démontrent qu'eIF4E pourrait réguler certaines réponses des cellules T CD4 d'une manière 4E-BP-dépendante ou -indépendante. Le ciblage précis d'eIF4E affecte significativement les propriétés fonctionnelles des cellules T, ce qui pourrait ouvrir une nouvelle ère pour le traitement thérapeutique de certaines maladies auto-immunes.
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Vasavda, Nisha. "Steroid dependent asthma : gene expression changes in T-lymphocytes and functional consequences." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405899.
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Ito, Kosei. "c-Jun stimulates origin-dependent DNA unwinding by polyomavirus large T antigen." Kyoto University, 1997. http://hdl.handle.net/2433/202211.
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Klemetti, Paula. "T-cell mediated immunity in the pathogenesis of insulin-dependent diabetes mellitus." Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/klemetti/.
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Hoellman, John Richard. "Contact-Dependent Activation of Macrophages by Naive CD4+ T cells." [Johnson City, Tenn. : East Tennessee State University], 2000. http://etd-submit.etsu.edu/etd/theses/available/etd-0602100-130806/restricted/electhesisJU21c.pdf.
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Tamang, David L. "Modulation of T lymphocyte cytotoxic potential." abstract and full text PDF (free order & download UNR users only), 2008. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3307587.
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Kapoor, Varun N. "Tissue-dependent T Cell Apoptosis and Transcriptional Regulation of Memory CD8+T Cell Differentiation During Viral Infections: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/691.
Full textAbstract:
Activation and proliferation of antigen-specific T cells is the hallmark of an anti-viral immune response. Effector T cells generated during an immune response are heterogeneous in regards to their ability to populate the memory pool once the immune response has resolved. Initial T cell activation takes place in the lymphoid organs, after which T cells migrate into the non-lymphoid tissues. The presence of memory T cells at non-lymphoid tissue sites has been shown to be critical for protection against secondary virus challenge. Our lab has previously demonstrated that during and after the resolution of the immune response to Lymphocytic choriomeningitis virus (LCMV) CD8+T cells in the nonlymphoid tissues are more resistant to apoptosis than those in the lymphoid organs. This stability of T cells in the non-lymphoid tissues may be critical in ensuring protection against a secondary virus challenge.
Mechanisms regulating tissue-dependent differences in CD8+T cell apoptosis were studied in an acute LCMV infection model. Virus-specific CD8+T cells from lymphoid (spleen, mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN)) and non-lymphoid tissues (peritoneal exudate cells (PEC), fat-pads) were compared for expression of surface antigenic markers known to correlate with a memory phenotype. Non-lymphoid tissues were enriched in IL-7Rhi, KLRG-1lo, CD27hi and CXCR3hi virus-specific CD8+ T cells, and the presence of these antigenic markers correlated with increased memory potential and survival. Transcription factors in addition to cell surface antigens were assessed as correlates of resistance to apoptosis. Virus-specific CD8+T cells in the nonlymphoid tissues were enriched in cells expressing T cell factor-1 (TCF-1), which correlated with increased memory potential and survival. CD8+T cells in the peritoneum of TCF-1-deficient mice had decreased survival during resolution of the immune response to LCMV, suggesting a role for TCF-1 in promoting survival in the non-lymphoid tissues.
As an additional mechanism, I investigated whether apoptosis-resistant CD8+T cells migrate to non-lymphoid tissues and contribute to tissue-dependent apoptotic differences. CXCR3+ CD8+T cells resisted apoptosis and accumulated in the lymph nodes of mice treated with FTY720, which blocks the export of lymph node cells into the peripheral tissues. The PECs expressed increased amounts of CXCR3 ligands, CXCL9 and CXCL10, which may have recruited the non-apoptotic cells from the lymph nodes. By adoptively transferring splenic T cells into the spleen or PEC environment I showed that the peritoneal environment through a yet undefined factor promoted survival of CD8+T cells. In this study I have elucidated the mechanisms by which CD8+T cells preferentially survive in the non-lymphoid tissues. I found that non-lymphoid tissues were enriched in memory-phenotype CD8+T cells which were intrinsically resistant to apoptosis irrespective of the tissue environment. Furthermore, apoptosisresistant CD8+T cells may preferentially migrate into the non-lymphoid tissues where the availability of tissue-specific factors may enhance memory cell survival.
Few transcription factors have been identified that regulate CD8+T cell effector-memory differentiation during an immune response. In this thesis, I have also studied the mechanism by which the transcription factor Blimp-1 regulates the generation of effector and memory CD8+T cells. Blimp-1 is known to repress a large number of target genes, and ChIP (chromatin immunoprecipitation) sequencing analysis done by Dr. HyunMu Shin in the lab of Dr. Leslie J. Berg identified CD25 (IL-2Rα) and CD27 as potential targets of Blimp-1. I found that Blimp-1-deficient CD8+T cells had sustained expression of CD25 (IL-2Rα) and CD27 during peak and resolution of the immune response to LCMV. By performing adoptive transfers of CD25hi and CD27hi CD8+T cells I showed that CD25 and CD27 expression on CD8+T cells during resolution of the immune response correlates with enhanced survival. Silencing Il2rα and Cd27 expression reduced the Blimp-1-deficient CD8+T cell response, suggesting that sustained expression of CD25 and CD27 was in part responsible for the enhanced CD8+T cell response seen in the Blimp-1-deficient mice. Furthermore, our collaborator Dr. HyunMu Shin showed that CD25 and CD27 are direct targets of Blimp-1, and that Blimp-1 recruits histone modifying enzymes to Il2rα and Cd27 loci to suppress their expression during the peak of the anti-viral immune response. This study identifies one of the mechanisms by which Blimp-1 regulates the balance between generation of effector and memory CD8+T cells.
In this thesis work I also studied the function of the transcription factor ROG (Repressor of GATA-3) in regulating in vivo T cell responses during both acute and chronic LCMV infection. ROG-deficient mice had increased CD8+T cell responses during an acute LCMV infection. ROG deficiency also led to the generation of memory T cells with an enhanced recall response compared to WT controls. By using LCMV-specific P14+ TCR transgenic ROG-deficient CD8+T cells these defects were shown to be T cell intrinsic. ROG-deficient mice had enhanced CD8+T cell responses and viral clearance during a persistent high dose LCMV Clone 13 infection. During chronic LCMV infection ROG-deficient mice also had increased lung pathology and mortality. The results indicate that ROG negatively regulates T cell responses and memory generation during both acute and chronic LCMV infection.
The studies highlighted in this thesis elucidate the mechanisms promoting CD8+T cell survival in non-lymphoid tissues as well as transcription factormediated regulation of memory CD8+T cell differentiation. Knowledge of this will help us better understand T cell immunity after infections and may eventually help develop better vaccines.
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Lam, Eric M. "IDENTIFICATION OF CYCLIN-DEPENDENT KINASE 5 IN T CELLS AND ITS ROLE IN REGULATING T CELL FUNCTION AND DIFFERENTIATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1422014852.
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Kapoor, Varun N. "Tissue-dependent T Cell Apoptosis and Transcriptional Regulation of Memory CD8+T Cell Differentiation During Viral Infections: A Dissertation." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/691.
Full textAbstract:
Activation and proliferation of antigen-specific T cells is the hallmark of an anti-viral immune response. Effector T cells generated during an immune response are heterogeneous in regards to their ability to populate the memory pool once the immune response has resolved. Initial T cell activation takes place in the lymphoid organs, after which T cells migrate into the non-lymphoid tissues. The presence of memory T cells at non-lymphoid tissue sites has been shown to be critical for protection against secondary virus challenge. Our lab has previously demonstrated that during and after the resolution of the immune response to Lymphocytic choriomeningitis virus (LCMV) CD8+T cells in the nonlymphoid tissues are more resistant to apoptosis than those in the lymphoid organs. This stability of T cells in the non-lymphoid tissues may be critical in ensuring protection against a secondary virus challenge.
Mechanisms regulating tissue-dependent differences in CD8+T cell apoptosis were studied in an acute LCMV infection model. Virus-specific CD8+T cells from lymphoid (spleen, mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN)) and non-lymphoid tissues (peritoneal exudate cells (PEC), fat-pads) were compared for expression of surface antigenic markers known to correlate with a memory phenotype. Non-lymphoid tissues were enriched in IL-7Rhi, KLRG-1lo, CD27hi and CXCR3hi virus-specific CD8+ T cells, and the presence of these antigenic markers correlated with increased memory potential and survival. Transcription factors in addition to cell surface antigens were assessed as correlates of resistance to apoptosis. Virus-specific CD8+T cells in the nonlymphoid tissues were enriched in cells expressing T cell factor-1 (TCF-1), which correlated with increased memory potential and survival. CD8+T cells in the peritoneum of TCF-1-deficient mice had decreased survival during resolution of the immune response to LCMV, suggesting a role for TCF-1 in promoting survival in the non-lymphoid tissues.
As an additional mechanism, I investigated whether apoptosis-resistant CD8+T cells migrate to non-lymphoid tissues and contribute to tissue-dependent apoptotic differences. CXCR3+ CD8+T cells resisted apoptosis and accumulated in the lymph nodes of mice treated with FTY720, which blocks the export of lymph node cells into the peripheral tissues. The PECs expressed increased amounts of CXCR3 ligands, CXCL9 and CXCL10, which may have recruited the non-apoptotic cells from the lymph nodes. By adoptively transferring splenic T cells into the spleen or PEC environment I showed that the peritoneal environment through a yet undefined factor promoted survival of CD8+T cells. In this study I have elucidated the mechanisms by which CD8+T cells preferentially survive in the non-lymphoid tissues. I found that non-lymphoid tissues were enriched in memory-phenotype CD8+T cells which were intrinsically resistant to apoptosis irrespective of the tissue environment. Furthermore, apoptosisresistant CD8+T cells may preferentially migrate into the non-lymphoid tissues where the availability of tissue-specific factors may enhance memory cell survival.
Few transcription factors have been identified that regulate CD8+T cell effector-memory differentiation during an immune response. In this thesis, I have also studied the mechanism by which the transcription factor Blimp-1 regulates the generation of effector and memory CD8+T cells. Blimp-1 is known to repress a large number of target genes, and ChIP (chromatin immunoprecipitation) sequencing analysis done by Dr. HyunMu Shin in the lab of Dr. Leslie J. Berg identified CD25 (IL-2Rα) and CD27 as potential targets of Blimp-1. I found that Blimp-1-deficient CD8+T cells had sustained expression of CD25 (IL-2Rα) and CD27 during peak and resolution of the immune response to LCMV. By performing adoptive transfers of CD25hi and CD27hi CD8+T cells I showed that CD25 and CD27 expression on CD8+T cells during resolution of the immune response correlates with enhanced survival. Silencing Il2rα and Cd27 expression reduced the Blimp-1-deficient CD8+T cell response, suggesting that sustained expression of CD25 and CD27 was in part responsible for the enhanced CD8+T cell response seen in the Blimp-1-deficient mice. Furthermore, our collaborator Dr. HyunMu Shin showed that CD25 and CD27 are direct targets of Blimp-1, and that Blimp-1 recruits histone modifying enzymes to Il2rα and Cd27 loci to suppress their expression during the peak of the anti-viral immune response. This study identifies one of the mechanisms by which Blimp-1 regulates the balance between generation of effector and memory CD8+T cells.
In this thesis work I also studied the function of the transcription factor ROG (Repressor of GATA-3) in regulating in vivo T cell responses during both acute and chronic LCMV infection. ROG-deficient mice had increased CD8+T cell responses during an acute LCMV infection. ROG deficiency also led to the generation of memory T cells with an enhanced recall response compared to WT controls. By using LCMV-specific P14+ TCR transgenic ROG-deficient CD8+T cells these defects were shown to be T cell intrinsic. ROG-deficient mice had enhanced CD8+T cell responses and viral clearance during a persistent high dose LCMV Clone 13 infection. During chronic LCMV infection ROG-deficient mice also had increased lung pathology and mortality. The results indicate that ROG negatively regulates T cell responses and memory generation during both acute and chronic LCMV infection.
The studies highlighted in this thesis elucidate the mechanisms promoting CD8+T cell survival in non-lymphoid tissues as well as transcription factormediated regulation of memory CD8+T cell differentiation. Knowledge of this will help us better understand T cell immunity after infections and may eventually help develop better vaccines.
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Fox, Casey John. "Genetic regulation of contingent macrophage- and T-cell-dependent steps in islet inflammation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0016/NQ45721.pdf.
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Saoulli, Catherine. "CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0008/MQ40765.pdf.
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Pennavaria, Stefanie [Verfasser], and Reinhard [Akademischer Betreuer] Obst. "mTORC1-dependent RNA synthesis in proliferating T cells / Stefanie Pennavaria ; Betreuer: Reinhard Obst." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1193423236/34.
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Sato, Kyosuke. "Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+ T cells." Kyoto University, 2018. http://hdl.handle.net/2433/232074.
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Cho, Sehyun. "Evaluation of the age-dependent role of natural killer t cells in gammaherpesvirus infection." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/56494.
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Epstein-Barr virus (EBV), a human gammaherpesviruses, demonstrates age dependent-
pathogenesis. EBV infection in young children is usually asymptomatic, whereas primary EBV infection later in life frequently results in the development of infectious mononucleosis (IM) due to uncontrolled expansion of CD8⁺ T lymphocytes. Natural killer (NK) T cells are innate T lymphocytes that respond to various pathogens through recognition of lipid antigens presented by CD1d receptors. Previous findings suggested that NKT cells have cytotoxic effects on EBV-infected cell lines. Furthermore, infection with other herpesviruses such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and herpes simplex virus (HSV) can modulate the host immune response to evade NKT cells. To explain the age dependence of EBV pathogenesis, we hypothesized that there is an early window of opportunity to control gammaherpesvirus infection by invariant NKT cells. To test our hypothesis, we infected both neonatal and adult wild type and CD1d knock out (CD1d KO) C57BL/6 mice with murine gammaherpesvirus 68 (MHV-68). Our readout was the quantification of virus copy number by qPCR from genomic DNA extracted from lung and spleen. We report that there was no significant difference in symptoms and viral load between adult and young C57BL/6 and CD1dKO mice. We conclude that NKT cells do not have a major role in the control of gammaherpesvirus infection. The inability of NKT cells to control MHV-68 infection may be due to virus-mediated downregulation of CD1d expression on B cells.<br>Medicine, Faculty of<br>Medicine, Department of<br>Experimental Medicine, Division of<br>Graduate
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Schilke, Angela J. "The parameters of Cyclosporine A induced inhibition of a T cell dependent antibody response." Virtual Press, 1990. http://liblink.bsu.edu/uhtbin/catkey/724567.
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Cyclosporine A (CsA) is a widely used immunosuppressive drug which has novel, clinically beneficial effects on the immune system. Substantial evidence indicates that CsA acts preferentially by impairing T cell lymphokine production, but there is some evidence that CsA may also affect B cells and other antigen presenting cells directly. Using an in vitro antibody response to sheep red blood cells, we have examined the effect CsA has on different populations of mouse lymphocytes. CsA appears to have a direct inhibitory effect on highly purified B cells from naive animals in a dose dependent manner at physiologically achievable levels in vitro. Even antigen stimulated B cells were found to be sensitive to the late addition of CsA when the drug was added simultaneously with lymphokine. B cells and T cells briefly pulsed with CsA do not recover to produce antibody when CsA is removed. Indeed, B cells from naive animals treated in vivo with CsA and stimulated in vitro with lymphokine and SRBC to produce antibody are profoundly inhibited from producing PFC despite the absence of CsA in culture. These findings suggest that CsA has direct irreversible, fast acting inhibitory effects on B lymphocytes aside from or in addition to its effects on T cells.<br>Department of Biology
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Turney, Abigail. "Bacterial polysaccharides and their free-radically degraded products in T-cell dependent immunological responses." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394719.
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Mori, Masato. "Cell-contact dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts." Kyoto University, 2017. http://hdl.handle.net/2433/218010.
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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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Lu, Kun-Hui [Verfasser], and Bernd [Akademischer Betreuer] Arnold. "On the Regulation of T Cell‐dependent Immune Responses / Kun-Hui Lu ; Betreuer: Bernd Arnold." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1180032772/34.
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Chen, Huaqing. "Covalent chemical events as costimulatory signals in T cell receptor-dependent activation of TH-cells." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267651.
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Huang, W. C. "NKG2D-dependent cross talk between NK cells and CD4 T cells in chronic hepatitis B." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1496146/.
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NK cells are emerging as potent regulators of adaptive immunity in virus infection. Our group recently documented the partially TRAIL-dependent deletion of HBV-specific T cells by NK cells. For this study, we investigated the underlying interactions between NK cells and T cells through the NKG2D pathway in chronic HBV infection. In this study, we observed that activated and HBV-specific T cells, especially the CD4 fraction, expressed NKG2D ligands (NKG2D-L) not normally seen on T cells. NKG2D-L upregulation was further enriched on CD4 T cells in HBV-infected livers compared to the circulation and control livers. Oxidative stress, one noteworthy pathogenic feature of HBV infection, was demonstrated to recapitulate the T cell NKG2D-L upregulation pattern seen in patients with chronic hepatitis B (CHB). NK cells from patients with CHB maintained NKG2D expression and their increased activation and cytotoxicity could be driven by NKG2D-L expressing cells. In line with the distinctive features of T cells and NK cells in CHB, we discovered a positive correlation between activation of NKG2D+NK cells and the NKG2D-L (MICA/B) levels on CD4 T cells. Additionally, the pro-inflammatory cytokine IFN-α, used in HBV treatment, was shown to favour for NKG2D-mediated regulation. To conclude, we provide the first ex vivo evidence that human T cells, particularly those sequestered within tissues, can become visible to the stress surveillance system by the induction of NKG2D-L. We show that in active CHB, T cells upregulate NKG2D-L which can drive NK cell activation and cytotoxicity via the NKG2D pathway. These interactions may be triggered by aberrant oxidative stress and result in a homeostatic response of "damage removal", thereby limiting T cell antiviral immunity. Therefore, efforts to manipulate the HBV-infected liver milieu in order to decrease T cell oxidative stress and diminish constraints from NK cells and the NKG2D pathway should be considered to reduce HBV pathogenesis and promote immunity.
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Hornung, Alexander. "Two-dimensional migration of human effector T-cells : integrin-dependent motility studies under shear stress." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4051/document.
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Bien que la description qualitative et phénoménologique de la migration cellulaire soient décrites de façon minutieuse dans son approche holistique, des mécanismes de base et connus depuis longtemps n’ont pas encore été explorés quantitativement avec une approche "bottom-up". Un de ces exemples est le comportement migratoire en deux dimensions des lym- phocytes T effecteurs humains. Alors que leur comportement in vivo est déjà connu depuis longtemps et décrit qualitativement, une approche quantitative in vitro offre de nombreuses perspectives. Les interactions des intégrines LFA-1 et VLA-4 avec leurs ligands respectifs ICAM-1 et VCAM-1 ont déjà été étudiées et sont les principales molécules impliquées dans la migration des lymphocytes T effecteurs. Du fait de leur importance dans l’organisation de la mobilité, ces deux protéines sont les principaux objets d’étude de cette thèse. La majorité des travaux précédents ont été réalisés en observant les lymphocytes T dans des tissus vi- vants dont la composition et la densité des molécules d’adhésion ne peuvent ni être déterminées ni contrôlées de façon précise. Nous avons developpés des substrats artifi- ciels permettant d’imiter et de contrôler ces caractéristiques adhésives afin d’examiner et de relier les propriétés physiques des cellules tels que la vitesse ou l’index de mi- gration orientée, avec une réponse cellulaire donnée ainsi que d’associer un type de mouvement avec des interactions intégrines-ligands spécifiques. Pour aller plus loin, nous avons à nouveau analysé la conformation des intégrines puis l’avons modulé pour altérer leur affinité et changer les propriétés précédemment décrites<br>The ability of T-lymphocytes to migrate to sites of inflammation towards all different types of tissues based on the interplay between biochemical and mechanical signaling is unique among human cells and underlines the importance of their complex motility apparatus relying on multiple stimuli. A crucial part within the leukocyte adhesion cascade is the firm attachment of the immune cell to the inner wall of the blood vessel and the subsequent migration along its surface until crossing the endothelial cell barrier. These migrational steps are guided not only by the shear stress to which the cell is exposed to by the flow of blood, but also by expression of adhesion molecules, the most important among them are ICAM-1 and VCAM-1 and their integrin counterparts LFA-1 and VLA-4, expressed by the immune cell. These proteins are crucial not only in a mechanically anchoring sense, but they also play a part in an intracellular signaling process leading to a change in migrational direction, overall cell affinity and phenotype. Few is known about how all components shape the movement behaviour on a quantitative level, raising questions about hierarchy, affinity and density of the involved proteins. Besides enhancing the general knowledge of the mechanisms of T-cell migration, the role of ICAM-1 and VCAM-1 in various diseases makes this study a promising endeavour. The approach taken in this thesis is to dissect and recompose the important adhesion molecules on a laminal flow chamber to link the cell’s response to them to specific movement properties and answer the questions addressed above
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Barron, Luke. "The roles of Bim-dependent apoptosis in controlling the responses of CD4+ T helper lymphocytes." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3261259.
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Phan, Tri Giang. "The SWHEL model for studying B cell responses in tolerance and immunity." University of Sydney. Medicine, 2005. http://hdl.handle.net/2123/626.
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Classical immunoglobulin transgenic (Ig-Tg) mouse models such as the MD4 anti-hen egg lysozyme (-HEL) Ig-Tg line have been used extensively to study B cell responses in tolerance and immunity. This thesis describes a new generation of gene-targeted mice (designated SWHEL mice) whereby the VH10 Ig variable gene encoding the HyHEL-10 specificity of the original anti-HEL Ig-Tg mouse was targeted to the Ig heavy chain locus. B cells in the SWHEL mouse are therefore capable of undergoing class switch recombination (CSR) and somatic hypermutation (SHM), representing a major advance on the original MD4 mouse model. SWHEL mice were found to not only contain a large population of HEL-specific (HEL+) B cells but also a significant population of non-HEL-binding (HEL-) B cells generated by VH gene replacement. HEL+ SWHEL B cells were found to belong to the B2 lineage and displayed high levels of surface IgM. Nevertheless, they matured normally and colonised the primary B cell follicle and marginal zone (MZ) of the spleen. The SWHEL model thus provided an opportunity to re-examine some of the original observations made in the MD4 system and also to extend these observations, particularly with regard to the regulation of CSR by self-reactive B cells. As expected, analysis of SWHEL B cells exposed to high avidity membrane-bound HEL revealed that they underwent clonal deletion in the bone marrow (BM). More interestingly, analysis of HEL+ B cells exposed to low avidity soluble HEL revealed that they were able to emigrate from the BM to the spleen as anergic B cells. However, unlike anergic MD4 B cells, anergic SWHEL B cells were reduced in frequency, displayed an immature B cell phenotype, were excluded from the follicle and had a reduced lifespan. Direct measurement of B cell antigen receptor (BCR) occupancy by HEL and the frequency of HEL- competitor B cells was combined with mixed BM irradiation chimeras to demonstrate unequivocally that the difference in phenotype and fate of HEL+ B cells in the two systems was due solely to competition from HEL- B cells. In addition, the SWHEL model of B cell self-tolerance was used to show that while self-reactive B cells were hypo-responsive to BCR stimulation, BCR-independent signals delivered via anti-CD40 plus IL-4 or lipopolysaccharide could trigger them to undergo CSR and secretion of potentially pathogenic isotype-switched autoantibodies. Finally, the SWHEL model was used to study the responses of adoptively transferred follicular (Fo) and MZ B cells to in vivo activation with HEL conjugated to sheep red blood cells (HEL-SRBC). These studies revealed that both HEL+ MZ and Fo B cells were capable of mounting a robust T cell-dependent IgG1 antibody response to HEL-SRBC. However, HEL+ MZ B cells did not efficiently localise to the T cell-B cell border following antigen engagement and preferentially migrated to the bridging channels and red pulp. In contrast, HEL+ Fo B cells rapidly localised to the T cell-B cell border and subsequently colonised numerous germinal centres. As a result, the rate and pattern of SHM by HEL+ Fo and MZ B cells was shown to be distinct, with preferential targeting of mutations to the second complementarity-determining region in the former and to the second framework region in the latter. Together these data indicate illustrate the value of the SWHEL model and its potential to greatly advance the current understanding of B cell responses in tolerance and immunity.
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Phan, Tri Giang. "The SWHEL model for studying B cell responses in tolerance and immunity." Thesis, The University of Sydney, 2004. http://hdl.handle.net/2123/626.
Full textAbstract:
Classical immunoglobulin transgenic (Ig-Tg) mouse models such as the MD4 anti-hen egg lysozyme (-HEL) Ig-Tg line have been used extensively to study B cell responses in tolerance and immunity. This thesis describes a new generation of gene-targeted mice (designated SWHEL mice) whereby the VH10 Ig variable gene encoding the HyHEL-10 specificity of the original anti-HEL Ig-Tg mouse was targeted to the Ig heavy chain locus. B cells in the SWHEL mouse are therefore capable of undergoing class switch recombination (CSR) and somatic hypermutation (SHM), representing a major advance on the original MD4 mouse model. SWHEL mice were found to not only contain a large population of HEL-specific (HEL+) B cells but also a significant population of non-HEL-binding (HEL-) B cells generated by VH gene replacement. HEL+ SWHEL B cells were found to belong to the B2 lineage and displayed high levels of surface IgM. Nevertheless, they matured normally and colonised the primary B cell follicle and marginal zone (MZ) of the spleen. The SWHEL model thus provided an opportunity to re-examine some of the original observations made in the MD4 system and also to extend these observations, particularly with regard to the regulation of CSR by self-reactive B cells. As expected, analysis of SWHEL B cells exposed to high avidity membrane-bound HEL revealed that they underwent clonal deletion in the bone marrow (BM). More interestingly, analysis of HEL+ B cells exposed to low avidity soluble HEL revealed that they were able to emigrate from the BM to the spleen as anergic B cells. However, unlike anergic MD4 B cells, anergic SWHEL B cells were reduced in frequency, displayed an immature B cell phenotype, were excluded from the follicle and had a reduced lifespan. Direct measurement of B cell antigen receptor (BCR) occupancy by HEL and the frequency of HEL- competitor B cells was combined with mixed BM irradiation chimeras to demonstrate unequivocally that the difference in phenotype and fate of HEL+ B cells in the two systems was due solely to competition from HEL- B cells. In addition, the SWHEL model of B cell self-tolerance was used to show that while self-reactive B cells were hypo-responsive to BCR stimulation, BCR-independent signals delivered via anti-CD40 plus IL-4 or lipopolysaccharide could trigger them to undergo CSR and secretion of potentially pathogenic isotype-switched autoantibodies. Finally, the SWHEL model was used to study the responses of adoptively transferred follicular (Fo) and MZ B cells to in vivo activation with HEL conjugated to sheep red blood cells (HEL-SRBC). These studies revealed that both HEL+ MZ and Fo B cells were capable of mounting a robust T cell-dependent IgG1 antibody response to HEL-SRBC. However, HEL+ MZ B cells did not efficiently localise to the T cell-B cell border following antigen engagement and preferentially migrated to the bridging channels and red pulp. In contrast, HEL+ Fo B cells rapidly localised to the T cell-B cell border and subsequently colonised numerous germinal centres. As a result, the rate and pattern of SHM by HEL+ Fo and MZ B cells was shown to be distinct, with preferential targeting of mutations to the second complementarity-determining region in the former and to the second framework region in the latter. Together these data indicate illustrate the value of the SWHEL model and its potential to greatly advance the current understanding of B cell responses in tolerance and immunity.
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Sharkey, Craig. "Stress-potentiated memory response to a second Escherichia coli injection is alpha/beta T-cell dependent." Diss., Connect to online resource, 2006. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1433510.
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Hirano, Ayumi. "T dependent B cell help in cattle : immunoregulatory function of interleukin-4 and CD40-CD40L interactions /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9841150.
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Wong, Voon Loong. "Computational studies of shear-dependent non-Newtonian droplet formation at microfluidics T-junction with experimental justification." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/28956/.
Full textAbstract:
When Reynolds number (Re) is typically small, the dominant forces governing droplet formation in a microfluidic system includes surface tension, viscous, adhesion, and inertial forces, and the rheology of fluid becomes significantly important when non-Newtonian fluids are involved. The aim of this thesis is to systematically investigate the non-Newtonian shear-thinning effect of sodium carboxymethylcellulose (CMC) on the physical process of droplet formation. A two-phase conservative level-set formulation is adopted to capture the droplets breakup dynamics and relevant hydrodynamics. Detailed two-dimensional (2D) computational microfluidics flow simulations were carried out to examine systematically the influence of different controlling parameters such as degree of shear-thinning (ηo/η∞), relaxation time (λCY), flow rates (Qc, Qd), viscosities (ηc, ηd), surface wettability (θ), and interfacial tensions (σ) on CMC microdroplets formation in a Newtonian continuum. Experimental tests and numerical model justification were performed in conjunction with grid refinement to support the computational analysis and ensure its accuracy and numerical stability. The breakup process of CMC microdroplets in the cross-flowing immiscible liquids in microfluidic device with T-shaped geometry was predicted well. Data for the rheological and physical properties obeying the Carreau-Yasuda stress model were experimentally obtained to support the computational work. In present study, it is worth noting that the dynamics of shear-thinning breakup process is very sensitive to the rheological quantities (ηo/η∞, λCY) under a range of typical shear rate that associated with microchannel. The systematic variation in these rheological quantities has demonstrated different velocity profile and droplet properties. This variation significantly affects the size of droplet and breakup regime, which has never been studied previously. In contrast to previous findings based on Newtonian solutions, the dependence of flow regimes, breakup time and generation frequency on CMC polymer concentration is distinctly different in dilute and semi-dilute concentration regimes, which only exists in polymer solutions. In dilute regimes, the breakup dynamics is similar to pure Newtonian solutions, which is droplet breakup sharply at the corner of T-Junction, as the polymers are at sufficiently low concentration. Conversely, in semi-dilute regime, the presence of highly polymer molecules leads to an elongated fluid thread, a delay in breakup time, and lower production rate of droplet. Interestingly, the existence of thin polymeric filament can be observed prior to breakup for shear-thinning solution. This feature is rarely observed in Newtonian solution, but a similar phenomenon that was previously attributed to elastic effects in the fluid. Besides, the instabilities in the filament leading to the formation and breakup of satellite droplets. In the view of essential role of interfacial tension, adhesion, viscous and inertial forces, the size of shear-thinning CMC droplets is always found to be smaller than the size of Newtonian droplets as it is believed that the shear-thinning thread encounter less resistance, resulting in rapid breakup phenomenon. Present investigations enhance the understanding of the polymer structural features that govern the droplet behaviour in different flow condition. This may contributes a conceptual framework to rheological application in pharmaceutical field, especially drug delivery system, which focuses on the stability and diffusion of drug particles in dispersion into the outer fluid.
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Gao, Yuanyuan. "Studies on CD40 Signaling-Unpreventable B Cell Receptor-Mediated Apoptosis in T Cell-Dependent Bystander B Cells." 京都大学 (Kyoto University), 2012. http://hdl.handle.net/2433/157848.
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Sepako, Enoch. "Influence of HIV and antiretroviral therapy on immunity to pneumococcal T-cell dependent antigens in Malawian adults." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569438.
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Background: Natural immunity to S. pneumoniae is thought to rely on antigen-specific T and B memory that can be rapidly mobilised to mediate microbial clearance at the mucosal surface as well as interrupt multiplication following invasion. HIV infection however increases the risk of invasive pneumococcal disease (IPD) and pneumococcal colonisation, suggesting that natural-acquired pneumococcal immunity is compromised in HIV infection. The aim of this research project was to investigate the effect of underlying HIV infection on naturally-acquired pneumococcal immunity in Malawian adults and the impact of antiretroviral therapy on this immunity. Additionally, the study evaluated the effect of HIV infection on immune memory mounted in response to vaccine protein antigens. Methods: Peripheral blood mononuclear cells obtained from HIV-uninfected and infected Malawian adults were stimulated with pneumococcal concentrated culture supernatants derived from a standard strain D39 wild-type, isogenic mutant strain lacking pneumolysin (Ply-) and diphtheria toxoid. In vitro immune responses to these antigens were assessed by CFSE proliferation, T and B ELISpot, surface expression of CD 154 and cytokine production by intracellular cytokine staining and bio-plex cytokine assays. Additionally, the proportion of T and B cell subsets including naive, memory, senescent and regulatory cells were determined using flow cytometry. Results: Circulating central memory (T CM) and naive (T N) CD4+ T cells were preferentially lost in asymptomatic HIV infection. There was also an over representation of senescent and regulatory T cells in HIV-infected adults. Pneumococcal-specific immune responses were either compromised (IFN-γ effector responses, proliferative and CD 154 expression) or altered (IF -γ/IL-I0) in asymptomatic HIV infection. HIV infection also increased the prevalence of nasopharyngeal colonisation in adults with advanced disease. There was some regeneration of pneumococcal specific CD4+ T cell responses including effector memory responses, proliferative capacity, CD154 pathway and ability to produce simultaneously multiple cytokines following initiation of ART. However, there was no regeneration of antigen-specific memory B cell responses. T and memory B cell responses to protein vaccine antigen (diphtheria toxoid) were compromised and appeared short-lived in HIV-infected persons well-established on ART. Conclusion: The data from this research project showed that HIV infection compromises systemic naturally-acquired pneumococcal immunity and that there is some regeneration of this immunity following initiation of ART. It is not known however whether the re- constituted immunity is long-term and protective. The data also suggests that immune memory to vaccine protein antigens is compromised in HIV-infected adults and possibly short-lived even in individuals stable on ART. These findings have important implications for clinical care of HIV-infected persons on ART and future studies on pneumococcal immunity in the context of HIV infection and therapy.
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Neideck, Carlos [Verfasser], and Christian [Akademischer Betreuer] Weber. "Ccl17-dependent release of Ccl3 restrains regulatory T cells thereby aggravating atherosclerosis / Carlos Neideck ; Betreuer: Christian Weber." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/119221532X/34.
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Stubblefield, Park Samantha Renee. "Organotypic brain explants reveal an interleukin-12 / interferon-γ / T-cell dependent clearance of measles virus infection". Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1297280439.
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Leutwyler, Christoph. "Interleukin-1[Beta] is necessary but not sufficient in anti-CD3-mediated monocyte-dependent T cell proliferation /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Leibfritz, Tobias Sebastian Verfasser], Angelika [Akademischer Betreuer] [Schnieke, and Jens T. [Akademischer Betreuer] Siveke. "JNKs are stress-dependent regulators of acinar maintenance and tumor suppressors in PDAC / Tobias Sebastian Leibfritz. Betreuer: Jens T. Siveke. Gutachter: Jens T. Siveke ; Angelika Schnieke." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1079001905/34.
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Anderson, Kathleen. "CD25+ CTLA-4+ T Cell-Dependent Induction of Anergic CD25- T Cells Limits the Immune Response to H. pylori Infection Resulting in Mild Gastritis and Persistent Colonization." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1144332338.
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Ng, Yifan. "Cell cycle-dependent and -independent mechanisms of T transcription in the mesodermal differentiation of human embryonic stem cells." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708648.
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