Dissertations / Theses on the topic 'Immune cell activation'
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1
Delcassian, Derfogail. "Biomimetic substrates for immune cell activation." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/30729.
Abstract:
This thesis describes the fabrication of biomimetic substrates, and their use as tools to probe cellular interactions of key immune cells. Nanoparticles of gold and zinc sulfide have been fabricated, and patterned into nanoarrays. Adaptive (T cell) and innate (NK cell) immune cell responses to nanoscale spacing of ligand-receptor pairs were measured, and the effect of presenting stimulatory ligands on substrates with varying mechanical properties has been tested for T cell responses. The advanced materials in this thesis act to create artificial immune synapses, and probe the effect of these stimuli on engagement and activation of human immune cells. Specifically, block co-polymers were used to form polymer micelles which encapsulate metal ions and form metal or metal compound nanoparticles. Micelles encapsulating metal ions or nanoparticles were formed and deposited onto substrates using Block Co-polymer Micellar Lithography (BCML) to form nanoparticle arrays with controlled inter-particle spacing. Well controlled gold nanoparticle arrays with spacing between 25-150nm have been produced. The technique has been further developed to include fabrication of zinc sulfide particles and nanoarrays. Zinc sulfide nanoparticles showed a unique internal structure with 5nm crystalline domains set in an amorphous matrix and an optical band gap of between 3.88-4.28eV. Nanoparticle arrays were then functionalised with biological ligands, notably antibodies that engage with the NK cell surface receptor CD16, or the T cell TCR/CD3 moiety. The cellular response to these materials was measured, and was sensitive to the nanoscale arrangement of stimulatory ligands; both cell types responded to ligands with 25nm, but not 104nm, inter-ligand spacing. In an alternative approach, spherical PEG hydrogel particles of diameter 5-50μm were formed with controlled rigidity between 3-2000kPa. T cell response as a function of substrate rigidity was tested, and cells showed maximal response to anti-CD3 functionalised substrates with rigidities of 3-5kPa.
2
Tilney-Bassett, Amanda L. "Phospholipid metabolism in T-cell activation." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239331.
3
Cliff, Jacqueline Margaret. "The role of autocrine factors in B cell activation." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327054.
4
Mohib, Kanishka. "Embryonic Stem Cell Extracts Possess Immune Modulatory Properties That Prevent Dendritic Cell Maturation and T Cell Activation." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22794.
Abstract:
Embryonic stem cells (ESC) possess immune privileged properties and have the capacity to modulate immune activation. ESCs can persist across allogeneic immunological barriers, prevent lymphocyte proliferation in mixed lymphocyte reaction (MLR) assays and can promote graft acceptance. However, clinical application of live ESC to treat immunological disorders is not feasible as live ESC can form teratoma in-vivo. In order to harness these properties of ESCs without adverse risk to patients, we hypothesized that ESC derived extracts may retain immune modulatory properties of whole cells and therefore could be used to abrogate allo-immune responses. We found addition of ESC-extracts from human lines H1 and H9, significantly prevented T cell proliferation in allogeneic MLRs. These results were confirmed using murine J1 ESC line. In-vitro studies showed human ESC EXT were able to modulate maturation of human monocyte derived dendritic cells (DC) by suppressing up-regulation of important co-stimulatory and maturation markers CD80, HLA-DR and CD83. In addition, DCs educated in the presence of human ESC extracts significantly lost their ability to stimulate purified allogeneic T cells compared to control extract treated DCs. We also determined that ESC extracts have an independent effect on T cells. ESC extracts prevented T cell proliferation in response to anti CD3/CD28 stimulation. In MLRs, ESC derived factors significantly down-regulated IL-2 and IFN-γ expression, while up-regulating TGF-β and Foxp3 expression. Furthermore, lymphocytes and purified T cells activated with anti-CD3/CD28, ConA and PMA proliferated poorly in the presence of ESC derived factors, while proliferation in response to ionomycin was not affected. Western blot analysis indicated that ESC derived factors prevented PKC-θ phosphorylation without influencing total PKC-θ levels. Moreover, IκB-α degradation was abrogated, confirming absence of PKC-θ activity. Therefore, ESC extracts have potent immune suppressive properties and may have clinical applications in ameliorating transplant rejection and autoimmune conditions.
5
Nugent, Alexandria Lynne. "Morphine activation of stress pathways alters peripheral immune cell signaling." Connect to Electronic Thesis (ProQuest), 2008. http://0-gateway.proquest.com.library.lausys.georgetown.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3315451.
6
Nyambuya, Tawanda Maurice. "Markers of chronic immune activation and T-cell function in hyperglycaemia." Thesis, Cape Peninsula University of Technology, 2017. http://hdl.handle.net/20.500.11838/2597.
Abstract:
Thesis (MTech (Biomedical Sciences))--Cape Peninsula University of Technology, 2017.Type 2 diabetes mellitus (T2DM) is a chronic inflammatory condition characterised by hyperglycaemia; continuous activation of T-lymphocytes and immune dysregulation. Although the exact mechanisms of these phenomena are not fully understood, there is strong evidence suggesting the involvement of T-cells in the chronic inflammatory environment which could predispose diabetics to infections and thrombotic events. The effect of hyperglycaemia on cells of the innate immune system in T2DM has been well described and implicated in the progression of the disorder and the development of its complications. However, studies investigating the adaptive immune response still remain scarce and controversial. Thus, investigating T-cells in hyperglycaemic conditions could provide further insight into the immune dysfunction observed in T2DM and assist in identifying pathways which could be targeted in the disease management and treatment. Therefore, this study aimed to investigate chronic immune activation by measuring the expression of T-cell activation markers in hyperglycaemia and compare the results to those in the normoglycaemic group.
7
Clary, Sara Reed. "The effects of nitrosoureas on Thymocyte differentiation and T cell activation." Thesis, Virginia Tech, 1990. http://hdl.handle.net/10919/41939.
8
Cantrell, Jessica. "Adjuvant Effect of Chaperone-Rich Cell Lysate: The Effects of CRCL on the Activation of Immune Cells." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195380.
Abstract:
Cancer immunotherapy aims to use and manipulate the host’s immune system to fight against cancer. The objective of this strategy is to induce specific and persistent immune responses leading to tumor eradication. Heat shock proteins (HSP) purified from cancer tissues have been identified as unique mediators of specific anti-tumor immunity. In our laboratory, we have developed an original vaccine, termed CRCL (Chaperone-Rich Cell Lysate) that consists of multiple HSP complexes enriched from tumor lysates. CRCL immunization leads to an efficient protection against a wide variety of murine cancers by inducing a strong, long-lasting, and specific T and NK-cell dependent immune responses against the tumor from which it has been generated. Tumor-derived CRCL has been shown to be more efficient in triggering DC activation than individual purified HSP or tumor lysates. The immunostimulatory effects of CRCL arise from its superior ability to provide a wide variety of tumor antigens to the immune system and by providing potent adjuvant effects. However, CD4⁺CD25⁺ regulatory T lymphocytes (Treg) critically contribute to the mechanisms of cancer-induced suppression. Data from independent groups including ours suggests they may also restrain the function of antigen presenting cells. The current study was designed to elucidate the molecular signaling events triggered by the tumor-derived CRCL vaccine in antigen presenting cells and evaluate whether CRCL may overcome the inhibitory effects of Treg modulation of DC and macrophage activation. Our results indicate CRCL activates DC and macrophages by inducing proinflammatory cytokine chemokine secretion. CRCL induces iNOS expression and NO production in macrophages. CRCL activation of DC and macrophages results in transcription factor NF-κB activation in vitro and in vivo, and this includes the activation of additional signaling molecules upstream of NF-κB. Following CRCL treatment the phenotypic maturation of DC, the production of DC and macrophage pro-inflammatory cytokines, and the activation of the transcription factor NF-κB are not affected by Treg. Additionally, CRCL induced activation of DC is not diminished by the immunosuppressive cytokine TGF-β 1. Our results indicate tumor-derived CRCL-treated DC and macrophages are refractory to Treg inhibition. These results are important for advancing CRCL-based vaccines in Phase I clinical trials.
9
Taner, Sabrina Beliz. "The role of lipid rafts in natural killer cell activation and immune surveillance." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423546.
10
Carlin, Lindsey Elizabeth. "Natural killer cell activation, trafficking, and contribution to immune responses to viral pathogens." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/1302.
Abstract:
Natural killer (NK) cells are a critical component of the immune response against viral infections. NK cell depletion prior to murine cytomegalovirus (MCMV) infections results in increased susceptibility to infection in several mouse strains. The mechanism of protection in C57Bl/6 mice is dependent on the activation of NK cells by Ly49H recognition of m157. Our previous studies have examined important residues of m157 for Ly49H recognition, as well as the contribution of m157 glycosylation to NK cell activation. However, what role the glycophosphatidyl inositol (GPI) anchor of m157 plays in Ly49H activation was unknown. Here we demonstrate that the GPI anchor of m157 regulates the surface expression of the protein. While the GPI anchor was not required for recognition of m157 by the activating or inhibitory Ly49 receptors, expression of GPI-anchored m157 resulted in greater receptor downregulation on NK cells, as well as increased NK cell cytotoxicity compared to transmembrane m157.
In addition to MCMV infections, NK cells have been shown to participate in the immune response to influenza A virus (IAV). However the exact role of NK cells in IAV infection is less clear, as some studies have found NK cells to be protective, while others have shown that NK cells cause lethal immunopathology. It is likely that the severity of IAV infection may dictate the NK cell response to IAV infection (i.e. protective vs. immunopathogenic). Herein we show that NK cell accumulation in IAV-infected lungs and lung-draining lymph nodes (DLN) is regulated by the severity of IAV infection, where there is increased NK cell accumulation in the lungs during high dose IAV infection, and greater NK cell accumulation in the DLN in low dose IAV infections. Despite significant NK cell recruitment to the lung during IAV infection, as well as previously published studies demonstrating the importance of NK cells to IAV immunity, NK cell depletion prior to IAV infection did not result in a significant change in morbidity or mortality. Interestingly, NK cell depletion resulted in a significantly greater number of CD4 T cells in the IAV infected lung. Further, both CD4 and CD8 T cells in NK-depleted mice showed increased IFN-Γ production. Finally, while not statistically significant, NK cell depletion resulted in a trend toward greater protection from heterosubtypic IAV challenge infections. Taken together these results suggest that NK cells may either regulate the adaptive immune response to IAV infection through suppression of CD4 and CD8 T cells, or that the T cell response to IAV infection is able to compensate for the loss of NK cells. Moreover, while NK cell suppression of T cell function during a primary IAV infection does not result in increased susceptibility to primary IAV infections, NK cell regulation of adaptive immune responses may suppress the memory T cell response, and therefore leave the host more susceptible to secondary infections.
Overall the studies presented herein demonstrate a complex role for NK cells in the immune response against viral infections. Ly49H+ NK cells directly kill MCMV-infected cells and m157-bearing targets, but NK cell activation is regulated by ligand density, as well as the ligand membrane anchor. Additionally, NK cells suppress adaptive immune responses during a primary IAV infection, resulting in changes to the T cell response during both primary and memory responses.
11
Freitas, Claudia Mercedes. "Regulation of Immune Cell Activation and Functionby the nBMPp2 Protein andthe CD5 Co-Receptor." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/8257.
Abstract:
According to the centers for disease control and prevention (CDC) and the world healthorganization (WHO), heart disease and immune related diseases such as diabetes and cancer areamong the leading causes of death around the world. Thus, the regulation of the function ofimmune cell plays a key role in health and disease. Calcium (Ca2+) ions play a critical role inimmune cell activation, function and in a robust immune response. Defects in Ca2+ signalinginfluences the development of cardiac disease, Alzheimer disease, immune cell metabolism,muscle dysfunction, and cancer. Each immune cell is unique in its activation and function,making it relevant to understand how activation of each type of immune cell is regulated. Herewe describe the role of the nBMP2 protein in macrophage activation and function and the role ofthe CD5 co-receptor in helper T cell activation and function.The nuclear bone morphogenetic protein 2 (nBMP2) is the nuclear variant of the bonemorphogenetic protein 2 (BMP2), a growth factor important in heart development, neurogenesis,bone, cartilage and muscle development. To better understand the function of nBMP2, transgenicnBMP2 mutant mice were generated. These mice have a slow muscle relaxation and cognitivedeficit caused in part by abnormal Ca2+ mobilization. Mutant nBMP2 mice also have an impairedsecondary immune response to systemic bacterial challenge. Here we have further characterizedmacrophage activation and function from mutant nBMP2 mice before and after bacterialinfection. We describe how nBMP2 influences the Ca2+ mobilization response and phagocytosisin macrophages, revealing a novel role of the nBMP2 protein in immune cell regulation.CD5 is a surface marker on T cells, thymocytes, and the B1 subset of B cells. CD5 isknown to play an important role during thymic development of T cells. CD5 functions as anegative regulator of T cell receptor (TCR) signaling and fine tunes the TCR signaling response.Here we describe our characterization of CD5 regulation of Ca2+ signaling in naïve helper Tcells. We also outline our findings examining how CD5-induced changes in helper T cellactivation influence other biological processes such as immune cell metabolism, the diversity ofthe gut microbiome, and cognitive function and behavior. Thus, this work elucidates theinfluence of the CD5 co-receptor on the functional outcomes in multiple systems when CD5 isaltered.
12
Smyth, Lucy J. C. "Activation of cells of the mast cell/basophil lineage in response to potential allergens in the absence of IgE sensitisation." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324450.
13
De, Milito Angelo. "Immune activation during HIV-1 infection : implication for B cell dysfunctions and therapy monitoring /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-170-5.
14
Alberghini, F. "THE ROLE OF PRC1 IN B CELL DEVELOPMENT AND ADAPTIVE IMMUNE RESPONSES." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/285499.
Abstract:
Polycomb (PcG) proteins are epigenetic modifiers that modulate accessibility of genomic loci by covalent modification of N-terminal histone tails. In mammals, PcG proteins act within at least two functionally and biochemically distinct complexes, named Polycomb repressive complex 1 and 2 (PRC1 and PRC2). Within PRC2, the Ezh2 methyltransferase is able to di- and tri-methylate lysine 27 of histone H3. This mark is recognized by chromodomain-containing PRC1 subunits. Once bound, PRC1 catalyzes monoubiquitination of lysine 119 of histone H2A, which results in permanent, yet reversible, and heritable locus silencing. PcG proteins modulate expression of genes involved in development, lineage specification and cell identity, and their deregulation leads to aberrant differentiation of a number of cellular lineages, including the hematopoietic subsets. Recently, independent studies on a number of PcG mutants have highlighted an essential contribution of the Polycomb system to homeostasis of the lymphoid lineage.
Expression of Ring1a and Ring1b, the catalytic subunits of PRC1, is maintained throughout B cell development. Using a conditional gene targeting approach in vivo, we addressed their function in resting naïve B lymphocytes and in B cells participating in a T cell-dependent immune response. Removal of a single subunit did not affect B cell development nor immune responses in mice. Instead, complete ablation of PRC1 function in B cells at early developmental stages resulted in a nearly complete block at the pro- to pre-B cell stage. Moreover, selective PRC1 inactivation in transitional B cells led to aberrant differentiation, with B cells acquiring features of mature cells while simultaneously retaining markers of earlier developmental stages. At the molecular level, loss of PRC1 in resting B cells read out in extensive transcriptional deregulation involving aberrant expression of several lineage determinants. Selective loss of Ring1a and Ring1b in GC B cells caused a significant reduction in numbers and frequency of GC B cells. As a result of the impaired GC reaction, serum titers of antigen-specific, class-switched antibodies were significantly decreased and formation of memory B cells significantly impaired in mutant mice. Instead, mutant GC B cells showed premature onset of terminal differentiation, as assessed by the induction of genes coding for the master regulators of plasma cell differentiation Prdm1, Irf4 and Xbp1. This result was confirmed by performing in vitro LPS stimulation assays, which showed an accelerated appearance of plasmablasts co-expressing Syndecan-1/CD138 and high levels of the Irf4 transcription factor in Ezh2 mutant B cell cultures. Increased apoptosis of PRC1 mutant cells as compared to control was also observed in the context of in vitro B cell activation. Importantly, activation of B cells with the RP105 Toll-Like Receptor agonist, which does not induce expression of Activation Induced Deaminase (AID) normalized the apoptotic rate of PRC1 deficient cells to wild-type levels. Moreover, several target genes of the germinal center master regulator Bcl6 were found up-regulated in PRC1 mutant cells. Together, this suggests that PRC1 may support GC function through at least two mechanisms. On the one hand, it may co-operate in establishing Bcl6 transcriptional program, thereby preventing premature terminal differentiation. On the other, it may participate in the repair of DNA damage caused by AID activity, thereby allowing tolerance of AID genotoxic activity by GC B cells.
15
Li, Hongbo. "SELECTIVE CB2 RECEPTOR ACTIVATION AMELIORATES INFLAMMATION IN CENTRAL NERVOUS SYSTEM BY REDUCING TH17 CELL DIFFERENTIATION AND IMMUNE CELL ACCUMULATION." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/288653.
Abstract:
PhysiologyPh.D.
Modulation of the endocannabinoid system by the administration of exogenous agonists and selective antagonists has been shown to have potential to attenuate the contribution of inflammation to secondary injury in the CNS. The two most well-defined receptors are the CB1 and CB2 receptors. CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in central nervous inflammation has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibited leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models; and our previous studies also demonstrated therapeutic potential of CB2 agonist improving recovery following spinal cord injury in the mouse. The goal of the current investigation was to evaluate the mechanisms through which administration of a selective cannabinoid-2 (CB2) agonist modifies inflammatory responses and helps to improve function following the injury in central nervous system. In the EAE project, we showed that Gp1a, a highly selective CB2 agonist with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In spinal cord injury project, we showed that spinal cord injury mice CB2 agonist O-1966 (with affinities to the CB1 and CB2 receptors of 5055±984 and 23±2.1 nM, respectively) had improved motor function, autonomic function. They also had significant reductions in CXCL-9, CXCL-11, dramatic reductions in IL-23p19 expression and its receptor IL-23r, and reduction in the number of immunoreactive microglia. The results reported in this thesis, demonstrated that the combined effect on Th17 differentiation and immune cell accumulation into the CNS, may contribute to the usefulness of CB2 selective ligands as potential therapeutic agents in neuroinflammation.
Temple University--Theses
16
Ehrenberg, Stefanie [Verfasser], and Josef [Akademischer Betreuer] Mautner. "Notch2 signalling in B cell activation, immune response and lymphomagenesis / Stefanie Ehrenberg. Betreuer: Josef Mautner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1096162849/34.
17
Patterson, Andrew R. "Gimap5: A Critical Regulator of CD4+ T Cell Homeostasis, Activation, and Pathogenicity." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1544098387129747.
18
Sousa, Daniela Alexandra Costeira de. "Stimulation of a pDC cell line with self-DNA immune complexes." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22095.
Abstract:
Mestrado em Biomedicina MolecularPlasmacytoid dendritic cells (pDCs) are a subset of Dendritic Cells that when stimulated can produce pro-inflammatory mediators and type I IFNs. These cells play an important role in autoimmune disease such as systemic lupus erythematosus, as they can become activated by immune complexes formed with self-DNA, which trigger a type I IFN response through the TLR-9 signaling pathway. Here, we optimized activation of CAL-1 cells, a human pDC cell line, with immunocomplexes of self-nuclear or mitochondrial DNA with the antimicrobial peptide LL37. It was found that high concentrations of LL37 led to a reduced CAL-1 cell viability. Self-DNA-LL37 triggered expression of IFN-α and IFN-β in CAL-1 cells, without inducing expression of TNF-α, as in primary pDCs. The concentrations of DNA and LL37 in the complexes leading to a stronger CAL-1 activation were 0.2μg/ml and 10μg/ml, respectively. We also found that CAL-1 cells stimulated with immune complexes with self-nuclear DNA, but not self-mitochondrial DNA, were capable of secreting the proinflammatory cytokine IL-1β. Immunocytochemistry analysis revealed that early endosomes and TLR-9 were recruited 30-60 minutes upon activation with immune complexes. Thus, this work established CAL-1 cells as a cell model for pDC activation with immune complexes.
As células dendríticas plasmacitóides (pDCs) são um subtipo de Células Dendríticas que quando estimuladas podem produzir mediadores proinflamatórios e IFNs do tipo I. Estas células desempenham um papel importante em doenças autoimunes como o lúpus sistémico eritematoso, uma vez que podem ser ativadas por imunocomplexos formados por DNA do próprio, que desencadeia uma resposta de IFNs do tipo I através da via de sinalização do TLR-9. Aqui, otimizamos a ativação das células CAL-1, uma linha celular de pDCs, com imunocomplexos de DNA nuclear ou mitocondrial do próprio com o péptido antimicrobiano LL37, em paralelo com a estimulação com CpG-A. Descobrimos que elevadas concentrações de LL37 reduzem a viabilidade celular das CAL-1. O próprio DNA-LL37 despoletam a expressão de IFN-α e IFN-β nas células CAL-1, sem induzir a expressão de TNF-α, tal como em pDCs primárias. As concentrações ideais de DNA e LL37 nos complexos que levam a uma forte ativação das CAL-1 são 0.2μg/ml e 10μg/ml, respetivamente. Também descobrimos que as células CAL-1 estimuladas com imunocomplexos de DNA nuclear do próprio, mas não de DNA mitocondrial do próprio, foram capazes de secretar a citocina pro-inflamatória IL-1β. A análise imunocitoquímica revelou que os endossomas iniciais e o TLR-9 são recrutados após ativação por 30-60minutos com imunocomplexos. Assim, este trabalho estabele as células CAL-1 como um modelo celular para a ativação de com imunocomplexos.
19
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.
20
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.
21
Schoggins, John Wesley. "Adenovirus host-cell interactions : the role of capsid proteins in transduction, immune activation, and gene targeting /." Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1432771281&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
22
Bhattarai, Nirjal. "GB virus C interactions with HIV: effects on immunoactivation and mechanisms of immunomodulation." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2437.
Abstract:
GB virus C (GBV-C) is a lymphotropic human virus which was recently assigned to a new genus Pegivirus within the Flaviviridae family. GBV-C infection is found worldwide, and viremia prevalence is about 1% to 4% in healthy blood donors and up to 42% in HIV-infected individuals. In clinical studies, GBV-C coinfection is associated with prolonged survival of HIV-infected individuals. GBV-C infection modestly alters T cell homeostasis in vivo through various mechanisms, including modulation of chemokine and cytokine release and receptor expression, and by diminution of T cell activation, proliferation and apoptosis, all of which may contribute to improved HIV clinical outcomes. This thesis explores the interrelationship between GBV-C infection and immunoactivation and identifies potential mechanisms by which GBV-C reduces immunoactivation.
Chronic HIV infection is associated with persistent immunoactivation which contributes to the immune dysfunction. In particular, T cell activation supports HIV replication and correlates with HIV viral load (VL). Persistent immunoactivation also contributes to the depletion of uninfected bystander cells by mechanisms of activation induced cell death (AICD). Although treatment with combination antiretroviral therapy (cART) reduces HIV VL, T cell activation does not return to levels found in HIVuninfected individuals. Sustained immunoactivation is also associated with lower virological response to cART suggesting therapies to reduce immunoactivation in combination with cART may benefit HIV-infected individuals. Since GBV-C infection is associated with reduced immunoactivation, understanding mechanisms by which GBV-C modulates these signaling pathways may provide insights into novel approaches to treat HIV infection and chronic immunoactivation.
The effect of GBV-C infection on T cell activation and IL-2 signaling pathways were studied in a cohort of HIV-positive individuals. GBV-C viremic HIV positive individuals on cART have reduced T cell activation which was significantly associated with higher percentage of immunomodulatory CD3 +CD4-CD8-T cells. Ex vivo GBV-C infection was associated with reduced lymphocyte proliferation in response to IL-2, lower frequency of reactivation of latent HIV and protection against AICD. In vitro expression of GBV-C envelope glycoprotein E2 in CD4+ T cell lines inhibited T cell receptor (TCR) induced IL-2 secretion and inhibited IL-2 signaling pathways. This effect was mediated at least in part by reducing activation of lymphocyte specific tyrosine kinase (Lck). Through deletion mutagenesis, the inhibitory motif within the viral protein was mapped to a region that contains a predicted Lck substrate, a highly conserved tyrosine at position 87 (Y87). Lck phosphorylated GBV-C E2 protein in vitro and mutation of Y87 residue abolished the inhibitory effects of E2 protein. Synthetic peptides containing this inhibitory motif competed for Lck phosphorylation and inhibited TCR signaling in primary human T cells. The number of GBV-C infected T cells was found to be low in vivo, yet GBV-C infection reduced global TCR signaling. GBV-C RNA and E2 protein were detected in extracellular microvesicles purified from GBV-C infected human serum or the culture supernatant of E2 expressing cells, and these microvesicles inhibited TCR signaling in uninfected bystander T cells. Together, these data identify a novel mechanism by which GBV-C infection leads to global reduction in T cell activation and IL-2 signaling in the infected host, and provide a working model in which the viral envelope glycoprotein serves as a substrate for Lck and competes for Lck phosphorylation in the infected T cells and in uninfected bystander T cells.
23
Hotchkiss, Kelly M. "Engineering Surface Properties to Modulate Inflammation and Stem Cell Recruitment through Macrophage Activation." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5492.
Abstract:
Biomaterials are becoming the most commonly used therapeutic method for treatment of lost or damaged tissue in the body. Metallic materials are chosen for high strength orthopaedic and dental applications. Titanium (Ti) implants are highly successful in young, healthy patients with the ability to fully integrate to surrounding tissue. However the main population requiring these corrective treatments will not be healthy or young, therefore further research into material modifications have been started to improve outcomes in compromised patients. The body’s immune system will generate a response to any implanted material, and control the final outcome. Among the first and most influential, cells to interact with the implant will be macrophages. Throughout this study we have 1) established the ability of macrophages to recognize and differentially activate in response to material surface properties, 2) investigated the role of integrin binding in macrophage activation to material properties, and 3) confirmed the importance of macrophage activation in vivo following Ti implant placement. The generation of a hydrophilic implant surface promoted the greatest anti-inflammatory and pro-regenerative macrophage activation. Surface wettability will control protein adsorption which can activated different integrin binding on macrophages and may be responsible for changes in activation. When integrin β3 subunit binding was prevented hydrophilic surfaces no longer promoted an anti-inflammatory macrophage activation. Additionally, when macrophage levels were reduced using two separate ablation models, MaFIA mice and clodronate liposomes, hydrophilic surfaces no longer promoted anti-inflammatory T-cell populations and cytokine profiles. There were also fewer stem cells adhered to implant surfaces at 1, 3, and 7 days when macrophage populations were compromised.
24
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.
Abstract:
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.
25
Reid, Timothy Dawson. "B lymphocyte activation and exhaustion in chronic HIV : novel surrogate markers of generalised immune activation and selective modulation of aberrant B cell responses using vasoactive intestinal peptide (VIP)." Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/96898.
Abstract:
Thesis (MScMedSc)--Stellenbosch University, 2015.ENGLISH ABSTRACT: Introduction: Chronic HIV-1 infection is characterized by immune activation and dysregulation of immune homeostasis, which impacts on multiple immune cell types. The B-cell compartment, which plays an important role in the producing neutralizing antibodies, is also dysregulated in HIV- 1 infection. In this study we investigated peripheral blood B-cell subset distribution, and changes in expression of cellular activation, inhibition, and apoptosis signaling markers in both untreated chronic HIV-1 infected individuals and healthy uninfected controls. The neuropeptide immune modulator, vasoactive intestinal peptide (VIP) is known to selectively down-regulate activation of CD4+ T-cells in various disease settings including HIV-1, however to our knowledge, no studies have investigated the effect of VIP inhibition on B-cell activation. Materials & Methods: A total of 21 HIV+ve (CD4 count >250 cells/µl), and 19 HIV-ve individuals were recruited from the Emavundleni voluntary testing and counseling clinic in Crossroads, Western Province, South Africa. Whole blood was stained to distinguish B-cell subsets (activated memory (AM: CD21-CD27+), resting memory (RM: CD21+CD27+), mature naïve (MN: CD21+CD27-), or tissue-like memory (TLM: CD21loCD27lo). In addition expression of markers of B-cell activation (CD126, CD86, CD38, CD284, CD287), inhibition (CD72, CD85j, CD300a, CD305, CD307d), and apoptosis signaling (CD95), was assessed ex vivo by flow cytometry (BD FACSCanto II). For determination of functional responsiveness isolated B-cells (RosetteSep, Stemcell Technologies) were cultured for 18h (37°C, 5%CO2) without stimulation or stimulated with TLR ligands (LPS or R848). Stimulation experiments were also performed in the presence or absence of VIP. Results: Chronic HIV-1 infection affected B-cell subset distribution. The percentage (%) of TLM was increased by 59.24%, and %RM was decreased by 22.73% (both p<0.01). Total expression of the VIP receptor VPAC2 was decreased by 47.35% (p=0.0296). Subsets had a mixed phenotype ex vivo; HIV infection upregulated CD38 (by 59.56%, p=0.0004), CD72 (by 60.70%, p=0.0396), CD307d (by 68.63%, p=0.0015) on AM, while RM B-cells had increased expression of TLR4 (by 107.04%, p=0.0057) and TLR7 (by 208.14%, p=0.0199). TLM B cells (i.e. exhausted phenotype) displayed upregulated TLR7 (by 550%, p=0.0128) and CD307d (by 72.40% p=0.045) expression. MN B-cells had increased CD72 expression (by 70.98%, p=0.0026). R848 upregulated CD86 expression by 42.20% on AM (p<0.01), and by 56.06% on RM B-cells (p<0.01), which was significantly downregulated with VIP inhibition (both p<0.05). Similarly, CD95 expression on RM, TLM, and MN B-cells increased by 31.10% (p<0.001), 21.46% (p<0.01), and 39.92% (p<0.01) with R848 stimulation respectively, which was also significantly downregulated with VIP inhibition. Conclusion: These data indicate that B-cells in untreated HIV infection display increased levels of activation, and also the potential for increased susceptibility to apoptosis as evidenced by increased FAS (CD95) expression. VIP significantly down-regulated markers of activation, inhibition, and apoptosis signaling. Dysregulation of B-cells is thus apparent in asymptomatic stable chronic HIV-1 infection, which may impact on both inefficient neutralizing antibody production and hypergammaglobulinemia. The ability of VIP to prevent stimulationassociated marker upregulation may indicate that VIP is a potential therapeutic agent. Its immuno-modulatory properties were demonstrated to limit B-cell hyperactivation, and selectively down-regulate apoptosis and mark it out for further investigation.
AFRIKAANSE OPSOMMING: Inleiding: Immunaktivering en ongekoppelde immuun-homeostase is kenmerke van chroniese MIVinfeksie. Ons het perifere bloed B-sel subgroep-verspreiding, en veranderinge in die uitdrukking van merkers van aktivering, inhibisie, en apoptose in 'n onbehandelde MIV-1 besmettende groep ondersoek (in vergelyk met 'n gesonde onbesmettende kontrole). Die immuun-moduleerder, vasoaktiewe intestinale peptied (VIP) is bekend om aktivasie van geaktiveerde CD4+ T-selle te verminder, maar tot ons kennis, is daar geen studies wat die effek van VIP-inhibisie op B-sel aktivering ondersoek het, in die konteks van MIV-1 infeksie. Materiaal & Metodes: MIV+we individue (CD4-telling >250 selle/µl) , en MIVwe kontroles is gewerf uit die vrywillige toetsing en berading Emavundleni kliniek, Crossroads, Westelike Provinsie, Suid-Afrika. Bsel subgroepe is gedefinieer as geaktiveerde geheue (AM: CD21- CD27+ ), rusende geheue (RM: CD21+ CD27+ ), volwasse naïef (MN: CD21+ CD27- ), of weefsel-agtige geheue (TLM: CD21loCD27lo). Merkers van aktivering (CD126, CD86, CD38, CD284, CD287), inhibisie (CD72, CD85j, CD300a, CD305, CD307d), en apoptose signalering (CD95) is via vloeisitometrie (BD FACSCanto II) op B-selle ex vivo en ook op geïsoleerde B-selle (RosetteSep, Cell Technologies) ondersoek. Vir die bepaling van funksionele responsiwiteit, geïsoleerde B-selle (RosetteSep, StemCell Technologies) was vir 18h (37°C, 5%CO2) gekweek, sonder stimulasie of gestimuleer met TLR ligande (LPS of R848). Stimulasie eksperimente het ook in die teenwoordigheid of afwesigheid van VIP plaasgevind. Resultate: Chroniese MIV-1 infeksie het B-sel subset verspreiding geraak. Die persentasie (%) van TLM is verhoog deur 59,24%, en% RM het met 22.73% afgeneem (beide p <0,01). Totale uitdrukking van die VIP reseptor VPAC2 het met 47,35% afgeneem (p = 0,0296). Subgroepe het 'n gemengde ex vivo fenotipe; MIV-infeksie het CD38 (deur 59,56%, p=0,0004), CD72 (deur 60,70%, p=0,0396), CD307d (deur 68,63%, p=0,0015) op AM verhoog, terwyl RM Bselle het verhoogde uitdrukking van TLR4 (deur 107,04%, p=0,0057) en TLR7 (deur 208,14%, p=0,0199). TLM B-selle (die uitgeputtende fenotiep) het verhoogde TLR7 (deur 550%, p=0,0128) en CD307d (deur 72,40% p=0.045) uitdrukking gewys. MN B-selle het verhoogde uitdrukking van CD72 (deur 70,98%, p = 0,0026). R848 het CD86 uitdrukking op AM deur 42,20%, en op RM deur 56,06% toegeneem (beide p <0,01). Dit het met VIP inhibisie beduidend afgeneem (beide p <0.05). CD95 uitdrukking was soortgelyk verhoog op RM, TLM, en MN B-selle met 31.10% (p <0.001), 21,46% (p <0,01), en 39,92% (p <0,01) met R848 stimulasie. Al drie het beduidend afgeneem met VIP inhibisie. Gevolgtrekking: Hierdie data dui daarop dat B-selle in onbehandelde MIV-infeksie vertoon verhoogde aktiveringsvlakke, en ook die potensiaal vir verhoogde vatbaarheid vir apoptose soos bewys deur verhoogde uitdrukking van FAS (CD95). VIP het beduidend merkers van aktivering, inhibisie, en apoptose af-gereguleer. Wanfunksie van B-selle is dus in asimptomatiese stabiele chroniese MIV-1 infeksie duidelik, wat impak kan hê op beide oneffektiewe neutraliserende teenliggaampie produksie, en hiepergammaglobulinimie. Die vermoë van VIP stimulasie-verwante merker opregulasie te voorkom kan aandui dat VIP 'n potensiële terapeutiese agent is. VIP se immuno-moduleerende eiendomme is gedemonstreer om Bsel hieperaktiveering te beperk, en selektief apoptose afreguleer, en merk dit vir verdere ondersoek.
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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.
Abstract:
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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RAELI, LORENZO. "Effect of anti-TNF therapy on T cell activation and effector functions in patients with chronic inflammatory diseases." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/10634.
Abstract:
TNF-blocking therapy is successfully used in the treatment of immune-mediated and inflammatory diseases. Although the inhibition of inflammatory pathways in target tissues by anti-TNF therapy has been clearly described, the impact of TNF-blockade on peripheral T cell responses in humans is still unclear. Here we studied T cell effector functions in psoriasis patients before and after treatment with anti-TNF by measuring a wide panel of cytokines as well as cell division upon in vitro stimulation. In parallel, the modulation of T cell cytokine gene expression was evaluated in psoriatic skin lesions. Results clearly evidenced that TNF-blockade increases T cell cytokine responses, mainly Th1 and Th17, in peripheral lymphocytes upon stimulation. Importantly, TNF-blockade also induced a potent enhancement of IL-10 expression by different subsets of circulating leukocytes that was found to correlate with the clinical outcome of the therapy.
Despite the enhanced T cell cytokine responses in the peripheral circulation, in psoriatic skin lesions the overall effect of TNF-blockade was a diminished expression of Th1 and Th17 cytokine genes, paralleled by augmented expression of Il10.
These evidences indicate a negative regulatory role of TNF on T cell activation and effector functions and enlighten a new role for TNF-blockade in the up-regulation of IL-10 that may participate to the shut down of the inflammatory reaction. Ongoing work (1): TNF-blockade enhances T cell response to TcR stimulation. Ongoing work (2): Modulation of cytokine gene expression by TNF-therapy in intestinal mucosa of patients with Inflammatory Bowel Disease
28
Paranjape, Anuya. "MAST CELL ACTIVATION BY DIVERSE STIMULI CAN BE SUPPRESSED BY STEROID THERAPY AND TARGETING THE FYN-STAT5B CASCADE." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5069.
Abstract:
Mast cells are critical effectors of allergic disease that can be activated by numerous stimuli. We have examined mast cell control by the inflammatory cytokine, IL-33, as well as IgG. In the first study reported here, we found that the synthetic glucocorticoid, dexamethasone, potently and rapidly suppressed IL-33-induced cytokine production from murine bone marrow–derived and peritoneal mast cells, as well as human mast cells. Dexamethasone also antagonized IL-33-mediated enhancement of IgE-induced cytokine production and migration. Although dexamethasone had no effect on IL-33-induced phosphorylation of MAP kinases or NFκB p65 subunit, it antagonized AP-1 and NFκB-mediated transcriptional activity. Finally, intraperitoneal administration of dexamethasone completely abrogated IL-33-mediated peritoneal neutrophil recruitment and prevented plasma IL-6 elevation. These data demonstrate that steroid therapy may be an effective means of antagonizing the effects of IL-33 on mast cells in vitro and in vivo, acting partly by suppressing IL-33-induced NFκB and AP-1 activity. In the second study reported here, we found that Fcγ receptor crosslinkage activated the transcription factor Stat5B through a Fyn kinase-dependent pathway. We then showed that STAT5B is critical for IgG-induced cytokine production by mast cells but not macrophages. To expand these studies, we employed the K/BxN model of inflammatory arthritis, which has roles for mast cells and macrophages. In this model, Fyn or STAT5B deficiency only affected the arthritic flare that primarily depends on mast cell degranulation, without affecting the severity of the joint swelling. By contrast, Lyn kinase deficiency significantly exacerbated arthritis. These studies indicate a clinically relevant, lineage-restricted role for the Lyn/Fyn-STAT5 cascade. Collectively, our work demonstrates that mast cell activation by diverse stimuli can be suppressed by steroid intervention and selectively targeted by disrupting kinase-transcription factor pathways.
29
Wagner, Stephen Douglas. "Characterization of early activation of multi-isotypic antibody-producing B lymphocytes in the small intestine." CSUSB ScholarWorks, 1999. https://scholarworks.lib.csusb.edu/etd-project/3018.
30
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.
Abstract:
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.
31
Schmidt, Madelyn R. "Virus-Lymphocyte Interactions: Virus Expression Is Differentially Modulated by B Cell Activation Signals: A Dissertation." eScholarship@UMMS, 1991. https://escholarship.umassmed.edu/gsbs_diss/51.
Abstract:
It is shown here that the ability of B lymphocytes to act as supportive host cells for virus infections requires they be activated from the resting Gostage of the cell cycle. I have used a series of activation regimens, which allow B cells to progress to different stages in their activation/differentiation pathway toward antibody secretion, in order to evaluate the extent of activation required to support vesicular stomatitis or Newcastle disease virus infections.
At least three distinct phases during B cell activation which affected VSV infection were defined. Freshly isolated resting murine splenic B cells in the Go phase of the cell cycle do not support VSV, assessed by protein synthesis, infectious center formation, and PFU production. Small B cells cultured for 48 hours without stimulation still do not support VSV. B cells stimulated with the lymphokines found in Con A activated supernatants from splenic T cells or cloned T cell lines transited into the G1 phase of the cell cycle but remain refractory to VSV. These VSV non-supportive B cell populations do take up virus particles and transcribe viral mRNAs which can be translated in vitro, suggesting a translational block to VSV. B cells stimulated into the S phase of the cell cycle with anti-immunoglobulin synthesize VSV proteins and increased numbers of infectious centers, but only low level PFU synthesis (center) is observed. Co-stimulation with anti-Ig and lymphokines, which supports differentiation to antibody secretion, enhanced PFU synthesis without further increasing the number of infected B cells. LPS, which activates B cells directly to antibody secretion by a pathway different from anti-Ig, induced infectious centers, and PFUs at levels comparable to those seen when stably transformed permissive cell lines are infected. Co-stimulation of LPS activated B cells with the same lymphokine populations that enhance PFU production when anti-Ig is used as a stimulator suppresses PFU production completely, suggesting that anti-Ig and LPS activated B cells are differentially responsive to lymphokines.
NDV infection of murine B cells differed markedly from VSV infection, as all B cell populations examined gave a similar response pattern. NDV viral proteins were synthesized by B cells in each of the activation states previously described, even freshly isolated B cells. Infectious center formation increased up to 5-fold over the levels observed with unstimulated B cells after anti-Ig or LPS activation. However, PFU synthesis was low (center) for all B cell populations.
These results suggest that these two similar viruses may be dependent on different host cell factors and that these factors are induced for VSV but not NDV by the B cell activators employed here or that the process of infection of B cell by these two viruses induces different cellular responses.
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Nguyen, Lam. "Immune Activation Induces Telomeric DNA Damage, Reduces Memory Precursors, and Promotes Short-lived Effector T Cell Differentiation in Chronic HCV Infection." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3828.
Abstract:
Chronic hepatitis C virus (HCV) infection exhibits persistent high viral load, inducing T cells differentiation and dysfunction in chronically infected individuals. Recent longitude studies in both HCV specific- and bulk T cells reveal that chronic immune stimulation is the driving force for the impaired T cell functions, however, the underlying mechanisms remain elusive. Here, we show that peripheral CD4+ T cells from chronically HCV-infected patients exhibit lymphopenia with the reduction of naïve population and expansion of effector memory T cells. CD4+ T cells from HCV patient also display elevated activation markers. including HLA-DR, GLUT1, Granzyme B, and short-lived effector marker CD127- KLRG1+, whereas stem cell-liked transcription factor TCF1 and telomere sheterin subunit TRF2 are significant reduced, comparing to age- and gender-matched healthy controls. Mechanistically, ex vivo T cell differentiation revealed that CD4+ T cells from HCV patients exhibit PI3K/Akt/mTOR signaling hyperactivation upon TCR stimulation, favoring pro-inflammatory effector differentiation with TRF2 downregulation, rendering telomere dysfunction induced foci (TIFs) accumulation, resulting in telomeric DNA damage and cellular apoptosis. Importantly, exacerbation of telomere deprotection by knockdown of TRF2 expression in healthy T cells resulted in an increase in telomeric DNA damage and T cell apoptosis; whereas overexpression of TRF2 in HCV-T cells led to an alleviation of telomeric DNA damage and T cell death. Additionally, inhibition of Akt signaling during T cell activation can preserve precursor memory population, while limiting inflammatory effector expansion, DNA damage, and cell death. Taken together, these results suggest that modulation of immune activation by inhibiting Akt signaling and protection of telomeres by enforcing TRF2 expression could open new therapeutic strategies to balance adaptive immune responses in the setting of chronic immune activation and inflammatory in vulnerable populations such as chronically viral infected individuals.
33
Horne, Phillip Howard. "Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1188397900.
34
Chivero, Ernest Tafara. "Tropism of human pegivirus (formerly known as GB virus C) and host immunomodulation : insights into viral persistence." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1565.
Abstract:
Human Pegivirus (HPgV; originally called GB virus C) is an RNA virus within the Pegivirus genus of the Flaviviridae that commonly causes persistent infection. Worldwide, approximately 750 million people are infected with HPgV. No causal association between HPgV and disease has been identified; however, several studies found an association between persistent HPgV infection and prolonged survival of HIV-infected individuals that appears to be related to a reduction in host immune activation. HPgV replicates well in vivo (>10 million genome copies/ml plasma) but grows poorly in vitro and systems to study this virus are limited. Consequently, mechanisms of viral persistence and host immune modulation remain poorly characterized, and the primary permissive cell type(s) has not yet been identified. The overall goals of my thesis were to characterize HPgV tropism, effects of HPgV infection on host immune response and mechanisms of viral persistence.
Previous studies found HPgV RNA in T and B lymphocytes and ex vivo infected lymphocytes produce viral particles. To further characterize HPgV tropism, we quantified HPgV RNA in highly purified CD4+ and CD8+ T cells, including naïve, central memory, and effector memory populations, and in B cells (CD19+), NK cells (CD56+) cells and monocytes (CD14+) obtained from persistently infected humans using real time RT-PCR. Single genome sequencing was performed on virus within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4+ and CD8+ T lymphocytes (9 of 9 subjects), B lymphocytes (7 of 9), NK cells and monocytes (both 4 of 5). HPgV RNA levels were higher in naïve (CD45RA+) CD4+ cells than in central memory and effector memory cells (p<0.01). HPgV sequences were highly conserved between patients (0.117 ± 0.02 substitutions per site) and within subjects (0.006 ± 0.003 substitutions per site). The non-synonymous/synonymous substitution ratio was 0.07 suggesting low selective pressure. CFSE-labeled HPgV RNA-positive microvesicles (SEV) from serum delivered CFSE to uninfected monocytes, NK cells, T and B lymphocytes, and HPgV RNA was transferred to peripheral blood mononuclear cells (PBMCs) with evidence of subsequent viral replication. Thus, HPgV RNA-positive SEV may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.
Although HPgV infection reduces NK cell activation in HIV-infected individuals, the mechanism by which this occurs is not characterized. We studied HPgV effects on NK cell non-cytolytic function in HIV-infected people by measuring expression of IL-12 induced interferon gamma (IFNg) and cytolytic function by measuring K562 target-cell induced CD107a and granzyme B. IFNg expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects treated with combination antiretroviral therapy (p=0.02). In contrast, cytolytic NK cell functions were not affected by HPgV. Inhibition of IFNg was due to inhibition of tyrosine kinase (Tyk2) by HPgV envelope protein E2. HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited IL-12-mediated IFNg release by NK cells. Thus HPgV-E2 inhibits NK cell non-cytolytic functions. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV's ability to persist with high viral loads (>10 million genome copies/ml plasma) and reduce immune cell activation. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases.
35
Ringqvist, Emma. "Host-Pathogen Responses during Giardia infections." Doctoral thesis, Uppsala universitet, Mikrobiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-108980.
Abstract:
Giardia lamblia is a eukaryotic parasite of the upper small intestine of humans and animals. The infecting trophozoite cells do not invade the epithelium lining of the intestine, but attach to the brush border surface in the intestinal lumen. The giardiasis disease in humans is highly variable. Prior to this study, the molecular mechanisms involved in establishment of infection or cause of disease were largely uncharacterized. In this thesis, the molecular relationship between Giardia and the human host is described. The interaction of the parasite with human epithelial cells was investigated in vitro. Changes in the transcriptome and proteome of the parasite and the host cells, and changes in the micro-environment of the infection have been identified using microarray technology, and 1- and 2-Dimensional SDS-PAGE protein mapping together with mass spectrometry identification. The first large-scale description of cellular activities within host epithelial cells during Giardia infection is included in this thesis (Paper I). We identified a unique activation of the host immune response and induction of apoptosis upon infection by Giardia. Four important virulence factors of the parasite, directly linked to the success of Giardia infection, were characterized and are presented in Papers II and III. The parasite was shown to have immune-modulating capacities, and to release proteins during host-interaction that facilitate the establishment of infection. Additional putative virulence factors were found among Giardia genes transcriptionally up-regulated during early infection (Paper IV). In summary, this thesis provides important insights into the molecular mechanisms of the host-parasite interaction.
36
Massanella, Luna Marta 1983. "CD4 and CD8 T-cell activation reflect different pathogenic asprects in chronic HIV-treated subjects." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/85720.
Abstract:
La infecció pel virus de la immunodeficiència humana (VIH) provoca una deficiència progressiva del sistema immunològic, caracteritzada per una destrucció massiva de les cèl•lules T CD4 i, una activació i inflamació immune mantinguda. La Teràpia Antiretroviral de Gran Activitat (o TARGA) indueix una supressió sostinguda de la replicació viral en individus infectats pel VIH, i una reducció de l’activació immune, encara que no es normalitza comparat amb individus no-infectats. Les causes d’aquesta activació immune persistent malgrat la supressió viral són encara desconegudes. Els nostres resultats demostren una dicotomia en les forces que indueixen l’activació immune en els limfòcits T CD4 i CD8 en individus suprimits per la TARGA. La replicació residual del VIH indueix l’activació immune en les cèl•lules T CD8. Per aquest motiu, la intensificació de la TARGA amb raltegravir produeix una reducció específica però reversible de l’activació de les cèl•lules CD8; i per tant, aquestes cèl•lules semblen ser sensors de la replicació viral (en particular l’expressió de CD38). Curiosament, l’expressió de CD38 està sota el control dels interferons de tipus I, el que suggereix que el virus també controla altres respostes inflamatòries, i que aquestes respostes estan íntimament lligades als marcadors d’activació de les cèl•lules T CD8. Contràriament, en individus tractats, la persistència viral té pocs efectes en el compartiment de cèl•lules T CD4, que encara pateix les conseqüències de la depleció pre-TARGA i que determina la recuperació immune. De fet, l’activació de cèl•lules CD4 no es redueix després d’un any de intensificació amb raltegravir. En canvi, la resposta homeostàtica a la depleció de cèl•lules CD4 sembla induir l’activació en aquest compartiment, especialment en pacients tractats que presenten una resposta immunològica deficient malgrat una supressió viral completa (pacients immunodiscordants). Els nostres resultats demostren que els pacients immnodiscordant tenen un menor producció de novo de cèl•lules T CD4, i una major translocació microbiana, activació i mort cel•lular comparat amb pacients amb una bona recuperació immune; malgrat aquestes diferències la immunodiscordància sembla està associada a l’increment de la destrucció cel•lular. L’activació i inflamació persistent en aquests individus procura un ambient que accelera la l’esgotament de les cèl•lules T CD4 i la immunosenescència de la resta del sistema immunològic, contribuint a llarg termini amb les co-morbiditats i l’envelliment prematur. Per aquest motiu, és important determinar les causes de l’activació immune incrementada (i mort cel•lular), per definir les estratègies terapèutiques que poden ser útils per millorar la recuperació immune.Human immunodeficiency virus (HIV-‐1) infection causes a progressive impairment of the immune system, characterized by a massive CD4 T-‐cell depletion and sustained immune activation and inflammation. Highly active antiretroviral therapy (HAART) induces a sustained effective suppression of viral replication in HIV-‐infected subjects and reduces immune activation, but does not normalize it. The causes of this persistent immunehyperactivation despite viral suppression remain unknown. Our results show a dichotomy between CD4 and CD8 T-‐cell driving forces of immune activation in HIV-‐infected HAART-‐suppressed individuals. The low (but detectable) levels of residual replication drive immune activation in CD8 T-‐cell compartment. Therefore, raltegravir intensification of HAART results in specific and reversible reduction of CD8 T-‐cell activation, which seems to be a sensor of replication events (in particular CD38 expression). Interestingly, CD38 expression is under the control of Type I IFN, suggesting that the virus also controls inflammatory responses and that these responses are intimately linked to CD8 T-‐cell activation markers. Conversely, in treated individuals, viral persitence has low effects on CD4 T-‐cell compartment, which still show the consequences of pre-‐HAART depletion and determine immune recovery. In fact, CD4 T-‐cell activation is not reduced after one year of raltegravir intensification. Instead, the homeostatic response to CD4 T-‐cell depletion might drive activation in this compartment, particularly in HAART-‐treated individuals with satisfactory virological response but poor immune recovery (immunodiscordant subjects). Our results suggest that, even though immunodiscordant individuals showed lower CD4 T-‐cell production and higher microbial translocation, activation and cell death, immunodiscordance seems to be related to increased cell-‐destruction of CD4 T-‐cells. The persistent immune activation and inflammation in these subjects provide a milieu of accelerated immunoexhaustion of CD4 T-‐cells and immunosenescence of the whole immune system, contributing to long-‐term co-‐morbidities and accelerated ageing observed in these subjects. Therefore, determining the causes of this increased hyperactivation and cell-‐death may be important for the development of therapeutic strategies aiming to improve immune recovery.
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Loots, Stanley. "Erythrocyte apoptosis (erythroptosis) and anaemia in chronic HIV-1 infection : relationship with immune activation and viraemia." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85803.
Abstract:
Thesis (MScMedSc)-- Stellenbosch University, 2013.ENGLISH ABSTRACT: Chronic HIV-1 infection is characterized by extensive inflammation/immune activation and also by anaemia. Macrophages and neutrophils produce reactive oxygen species (ROS) which can cause damage to surrounding cells, including erythrocytes. Damaged erythrocytes may die by apoptosis (erythroptosis) or be tagged for clearance by monocytes/ macrophages. In this study we investigated HIV-1-associated anaemia and erythroptosis in asymptomatic, untreated HIV-1 infected individuals and how it relates to oxidative stress and immune activation.
AFRIKAANSE OPSOMMING: Chroniese MIV-1 infeksie word gekenmerk deur uitgebreide inflammasie/immuun aktivering en ook deur anemie. Makrofage en neutrofiele produseer reaktiewe suurstof spesies (ROS), wat kan skade aan omliggende selle, insluitend rooibloedselle veroorsaak. Beskadigde rooibloedselle kan sterf deur apoptose (erythroptosis) of gemerk vir klaring deur monosiete/makrofage. In hierdie studie het ons ondersoek MIV-1-verwante bloedarmoede en erythroptosis in asimptomatiese, onbehandelde MIV-1 besmette individue en hoe dit verband hou met oksidatiewe stres en immuun aktivering.
The Poliomyelitis Research Foundation (PRF
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Rehr, Manuela. "The impact of HIV-1 replication on generalized immune activation and virus-specific T cell responses : implications for HIV-1 phatogenesis /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17000.
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Seifried, Janna [Verfasser]. "Mechanisms of down-regulation of immune activation and B-cell responses in the natural hosts of simian immunodeficiency virus / Janna Seifried." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1027276873/34.
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Priyadharshini, Bhavana. "Regulation of Early T Cell Activation by TNF Superfamily Members TNF and FASL: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/494.
Abstract:
The instructive signals received by T cells during the programming stages of activation will determine the fate of effector and memory populations generated during an immune response. Members of the tumor necrosis factor (TNF) superfamily play an essential role in influencing numerous aspects of T cell adaptive immune responses including cell activation, differentiation, proliferation, survival, and apoptosis. My thesis dissertation describes the involvement of two such members of the TNF superfamily, TNF and FasL, and their influence on the fate of T cells early during responses to viral infections and to the induction of transplantation tolerance.
TNF is a pleiotropic pro-inflammatory cytokine that has an immunoregulatory role in limiting the magnitude of T cell responses during a viral infection. Our laboratory discovered that one hallmark of naïve T cells in secondary lymphoid organs is their unique ability to rapidly produce TNF after activation and prior to acquiring other effector functions. I hypothesized that T cell-derived TNF will limit the magnitude of T cell responses. The co-adoptive transfer of wild type (WT) P14 and TNF-deficient P14 TCR transgenic CD8+ T cells, that recognize the GP33 peptide of lymphocytic choriomeningitis virus (LCMV), into either WT or TNF-deficient hosts demonstrated that the donor TNF-deficient P14 TCR transgenic CD8+ T cells accumulate to higher frequencies after LCMV infection. Moreover, these co-adoptive transfer experiments suggested that the effect of T cell-derived TNF is localized in the microenvironment, since the TNF produced by WT P14 TCR transgenic CD8+ T cells did not prevent the accumulation of TNF-deficient P14 TCR transgenic CD8+ T cells. To determine if T cell-produced TNF is acting on professional APC to suppress the generation of virus-specific T cell responses, I performed co-adoptive transfer experiments with WT P14 TCR transgenic CD8+ and TNF-deficient P14 TCR transgenic CD8+ T cells into TNFR1/2 (1 and 2) deficient mice. These experiments demonstrated that the absence of TNFR1/2 signaling pathway in the host cells resulted in a greater accumulation of WT P14 TCR transgenic CD8+ T cells, thereby considerably diminishing the differences between donor WT P14 TCR transgenic CD8+ and donor TNF-deficient P14 TCR transgenic CD8+ T cells. The increased frequency and absolute numbers of WT P14 TCR transgenic CD8+ T cells in TNFR1/R2 deficient recipients suggests that one mechanism for the suppressive effect of T cell-derived TNF on antigen-specific T cells occurs as a result of TNFR signaling in the host cells. However, the donor TNF-deficient P14 TCR transgenic CD8+T cells still accumulated to higher frequency and numbers compared to their donor WT transgenic counterparts. Together, these findings indicate that T cell-produced TNF can function both in an autocrine and a paracrine fashion to limit the magnitude of anti-viral T cell responses.
Given the immunoregulatory role of TNF and the ability of peripheral naïve T cells to produce this cytokine, I questioned at what stage of development do T cells become licensed to produce this cytokine. The peripheral naïve T cell pool is comprised of a heterogeneous population of cells at various stages of development, a process that begins in the thymus and is completed after a post-thymic maturation phase in the periphery. I hypothesized that naïve T cells emigrating from the thymus will be competent to produce TNF only after undergoing a maturation process in the periphery. To test this hypothesis, I compared cytokine profiles of CD4+ and CD8+single positive (SP) thymocytes, recent thymic emigrants (RTEs) and mature-naïve (MN) T cells during TCR activation. SP thymocytes exhibited a poor ability to produce TNF when compared to splenic T cells despite expressing similar TCR levels and possessing comparable activation kinetics with respect to the upregulation of CD25 and CD69 following stimulation. The reduced ability of SP thymocytes to produce TNF correlated with a decreased level of detectable TNF message following stimulation when compared to splenic counterparts. Stimulation of SP thymocytes in the context of a splenic environment did not fully enable TNF production, suggesting an intrinsic defect in their ability to produce TNF as opposed to a defect in antigen presentation. Using a thymocyte adoptive transfer model, I demonstrate that the ability of T cells to produce TNF increases progressively with time in the periphery as a function of their maturation state. RTEs identified by the expression of green fluorescent protein (GFP) (NG-BAC transgenic mice), showed a significantly enhanced ability to express TNF relative to SP thymocytes, but not to the extent of MN T cells. Together, these findings suggest that TNF expression by naïve T cells is regulated via a gradual licensing process that requires functional maturation in peripheral lymphoid organs. This highlights the functional heterogeneity of the naïve T cell pool (with respect to varying degrees of TNF production) during early T cell activation that can contribute to the many subsequent events that shape the course of an immune response.
The productive activation of naïve T cells requires at least initial two signals; the first being through the TCR and the second is the engagement of co-stimulatory molecules on the surface of the T cells. T cells activated in the absence of co-stimulation become anergic or undergo cell death. Agents that block co-stimulation of antigen-specific T cells are emerging as an alternative to immunosuppressive drugs to prolong allograft survival in transplant recipients. Targeted blockade of CD154-CD40 interactions using a αCD154 monoclonal antibody (MR1) with a simultaneous transfusion of allogeneic splenocytes (donor specific transfusion or DST) efficiently induces tolerance to allografts. This co-stimulation blockade-induced tolerance is characterized by the deletion of host alloreactive T cells within 24 hours of treatment. Toll-like receptor (TLR) agonists abrogate tolerance induced by co-stimulation blockade by impairing the deletion of host alloreactive T cells and resulting in allograft rejection. The goal of my study was to determine the underlying molecular mechanisms that protect host alloreactive T cells from early deletion after exposure to TLR agonists. I hypothesized that TLR ligands administered during co-stimulation blockade regimen differentially regulate the expression of pro- and anti-apoptotic molecules in alloreactive T cells, during the initial stages of activation thereby preventing deletion.
To test this hypothesis, I used syngeneic bone marrow chimeric mice containing a trace population of alloreactive KB5 TCR transgenic CD8+ T cells (KB5 Tg CD8+ T cells) that recognize H-2Kb as an alloantigen. I show here that KB5-CD8+ T cells downregulate CD127 (IL-7R!) and become apoptotic as early as 12 hrs after co-stimulation blockade. In contrast, KB5 Tg CD8+ T cells from mice treated with bacterial lipopolysaccaride (LPS) during co-stimulation blockade failed to become apoptotic, although CD127 was downregulated. Examination of the mRNA expression profiles of several apoptotic genes in purified KB5 CD8+ T cells from mice treated with DST+anti-CD154 for 12 hrs revealed a significant upregulation of FasL mRNA expression compared to the untreated counterparts. However, in vitro FasL blockade or in vivo cytotoxicity experiments with mice deficient in Fas or FasL indicated that the Fas-FasL pathway might not be crucial for tolerance induction. Another pro-apoptotic molecule BIM was upregulated in alloreactive T cells during co-stimulation blockade. This suggests that both the Fas pathway and BIM may be playing complementary roles in inducing deletional tolerance. Although FasL expression was diminished in alloreactive T cells in the presence of LPS, BIM expression was not diminished, suggesting that alloreactive T cells may still be vulnerable to undergo apoptosis. Concomitantly, I also found that LPS treatment during co-stimulation blockade resulted in non-specific upregulation of Fas expression in alloreactive T cells and non-transgenic T cells (CD4+ and CD8+). I demonstrate here that treatment with Fas agonistic antibody in vitrofor 4 hours can selectively induce apoptosis of alloreactive T cells that were believed to be refractory to apoptosis during LPS treatment. I speculate that under these conditions, deletion may be occurring due to the involvement of both Fas and BIM. Further, the mRNA expression profile revealed interleukin-10 (IL-10) as a molecule induced in alloreactive T cells during LPS treatment. Analysis of serum confirmed the systemic expression of IL-10 protein in mice treated with LPS during co-stimulation blockade. I hypothesized that LPS-induced IL-10 can have an anti-apoptotic role in preventing the deletion of alloreactive T cells and mediating allograft rejection. Contrary to my hypothesis, I found that IL-10 KO mice rejected allogeneic target cells similar to their WT counterparts, suggesting that IL-10 may not be required for LPS-mediated abrogation of tolerance induction. In addition to the systemic induction of IL-10, LPS also induced cytokines such as interleukin-6 (IL-6), TNF and interferon-γ (IFN-γ).
These findings suggest that both Fas-FasL and BIM mediated apoptotic pathways may play complementary roles in inducing the early deletion of activated alloreactive T cells during tolerance induction. On the other hand, the mechanism of LPS mediated abrogation of tolerance induction can not be attributed to IL-10 alone as it may be playing a synergistic role along with other proinflammatory cytokines that may in turn result in the prevention of alloreactive T cell death during this process. Most importantly, these findings indicate that despite emerging from a pro-inflammatory cytokine milieu, alloreactive T cells are still susceptible to undergo Fas-mediated apoptosis during the first 24 hours after co-stimulation blockade and LPS treatment. Therefore, targeting the Fas-FasL pathway to induce deletion of alloreactive T cells during the peri-transplant period may still be a potential strategy to improve the efficacy of co-stimulation blockade induced transplantation tolerance during an environmental perturbation such as inflammation or infection.
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Judge, Chelsey J. "IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387.
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Rivière, Élodie. "Rôle des cellules épithéliales salivaires au cours du Syndrome de Sjögren primitif Salivary gland epithelial cells from patients with Sjögren’s syndrome induce B-lymphocyte survival and activation Interleukin-7/Interferon axis drives T-cell and salivary gland epithelial cell interactions in Sjögren’s syndrome." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS124.
Abstract:
Le syndrome de Sjögren primitif (SSp) est une maladie auto-immune caractérisée par une infiltration lymphocytaire des glandes lacrymales et salivaires conduisant à l’apparition d’un syndrome sec oculaire et buccal. L’objectif de ce travail était de comprendre le rôle des cellules épithéliales salivaires (CES) dans la physiopathologie du SSp, via, notamment, leurs interactions avec les lymphocytes B (LB) et les lymphocytes T (LT).Nous avons montré que les CES de SSp étaient capables d’induire une meilleure survie des LB comparées aux CES de sujets contrôles. L’interaction entre CES et LB était médiée principalement par la sécrétion de facteurs solubles. Notre hypothèse est que cette interaction implique plusieurs facteurs agissant en synergie. L’inhibition individuelle de ces facteurs solubles ne permettait pas, en effet, de bloquer l’effet de soutien des CES aux LB. En revanche, l’ajout de leflunomide, ou d’un inhibiteur de BTK ou d’un inhibiteur de PI3K a permis d’inhiber l’augmentation de viabilité des LB induite par les CES.Concernant l’interaction entre CES et LT, nous avons montré que les CES sécrètent de l’interleukine 7 (IL7) après stimulation par interféron (IFN) de type I ou II. Nous avons également montré que l’IL7 est capable d’induire la production d’IFN de type II par les LT, suggérant l’existence d’une boucle d’amplification entre IL7 et IFN. L’utilisation d’un anticorps monoclonal inhibant le récepteur de l’IL7 (anti-IL7R) permettait de diminuer l’expression de gènes IFN induits dans les glandes salivaires en culture.Ces mécanismes pourraient induire et/ou entretenir localement, d’une part l’hyper-activation lymphocytaire B chronique présente au cours du SSp et, d’autre part, la signature IFN décrite dans les glandes salivaires. Ainsi, ces résultats confirment l’hypothèse que les CES ont un rôle pathogène direct au cours du SSp. La meilleure compréhension de leurs mécanismes d’action pourrait permettre de définir de nouvelles stratégies thérapeutiques au cours du SSpPrimary Sjogren's syndrome (pSS) is an auto-immune disease characterized by a lymphocytic infiltration of lacrimal and salivary glands leading to an ocular and oral dryness. The objective of this work was to understand the role of salivary gland epithelial cells (SGECs) in the pathophysiology of pSS and especially via their interactions with B and T lymphocytes. We observed a differential effect of SGECs from pSS and controls subjects since, in coculture, SGECs from pSS were able to induce a better survival of B lymphocytes compared to SGECs from controls. The interaction between SGECs and B lymphocytes involved mainly soluble factors. Our hypothesis is that several factors are involved and act in synergy. Indeed, inhibition of one of each soluble factor individually did not block the support of SGECs to B lymphocytes. In contrast, the addition of leflunomide, or a BTK inhibitor or a PI3K inhibitor inhibited the induction of B lymphocytes viability by SGECs.Regarding the interactions between SGECs and T lymphocytes, we showed that SGECs secrete interleukin 7 (IL7) after type I or II interferon (IFN)stimulation. In turn, IL7 is able to induce the production of type II IFN by T lymphocytes, suggesting the existence of an amplification loop between IL7 and IFN. The addition of a monoclonal antibody inhibiting the IL7 receptor (anti-IL7R) downregulated the expression of IFN induced genes in cultured salivary glands explants.These mechanisms could induce and/or maintain locally, the chronic B lymphocytes hyperactivation during pSS, as well as, the IFN signature described in the salivary glands. Thus, these results confirmed the hypothesis that SGECs play an active role in the pathogenesis of pSS. A better understanding of their mechanisms of action could help to define new therapeutic strategies in pSS
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Khairnar, Vishal S. [Verfasser], and Karl Sebastian [Akademischer Betreuer] Lang. "Role of Lymphotoxin Beta and Cell Adhesion Molecule (CEACAM1) in Innate and Adaptive Immune Activation / Vishal Shivajirao Khairnar ; Betreuer: Karl Sebastian Lang." Duisburg, 2017. http://d-nb.info/1137466618/34.
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Khairnar, Vishal Shivajirao [Verfasser], and Karl Sebastian [Akademischer Betreuer] Lang. "Role of Lymphotoxin Beta and Cell Adhesion Molecule (CEACAM1) in Innate and Adaptive Immune Activation / Vishal Shivajirao Khairnar ; Betreuer: Karl Sebastian Lang." Duisburg, 2017. http://d-nb.info/1137466618/34.
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Albergante, L. "A PETRI NET MODEL OF LIVER RESPONSE TO VISCERAL LEISHMANIASIS: SELF-REGULATION AND COMPLEX INTERPLAY IN THE VERTEBRATE IMMUNE SYSTEM." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150085.
Abstract:
Visceral leishmaniasis (also called "Kala-azar") is a widespread disease, which is usually fatal in the absence of treatment. Characteristic of the liver immune response to leishmaniasis is a type of inflammation (granulomatous inflammation) that leads to the formation of "granulomas". A granuloma provides a very interesting micro-environment, which is maintained by the coordination
of many cells of the immune system.
Due to the complexity of the immune response, only a limited amount of modeling work exists in the context of granulomatous infection, and most of the current models focus only on the formation stage of granulomas.
The primary goal of this thesis is to gain insights into the process of formation and development of a granuloma. To this end, we built a model of the granuloma formation and resolution in the liver using stochastic Petri nets, and performed several in silico experiments to study the nature of the immune response to leishmaniasis, possible therapeutic options, and the role of the cells involved.
Additionally, the building of the model is extensively documented, and the most important qualitative and quantitative assumptions are referenced and discussed, with the aim of presenting a “conceptual framework” to be used when facing similar problems. The model is validated against available biological data, and its robustness is assessed using sensitivity analysis.
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Bogner, Simon Sebastian [Verfasser], and Markus [Akademischer Betreuer] Glatzel. "Immune activation in Aβ-related angiitis (ABRA) and a cell model of E280A presenilin-mutated Familial Alzheimer's Disease / Simon Sebastian Bogner. Betreuer: Markus Glatzel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1059859823/34.
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Chung, Charlotte Yuk-Yan. "Tight Junctions - The Link Between HIV-Associated Intestinal Barrier Dysfunction and Loss of Immune Homeostasis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1417822947.
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Samassa, Fatoumata. "New insights into the manipulation of the host adaptive immune response by Shigella : the immunological synapse as a target." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC293.
Abstract:
La manipulation de la réponse immunitaire innée au cours des infections bactériennes a été largement documentée contrairement à celle de la réponse adaptative. C’est le cas de l’entérobactérie à Gram-négatif Shigella qui est l’agent causal de la dysenterie bacillaire, une rectocolite aiguë. L’inflammation due à l’invasion de la muqueuse colique et la destruction qui en résulte reposent sur l’expression d’un Système de Sécrétion de Type Trois (SST3) par Shigella. Ce système assure l’injection d’effecteurs de virulence bactériens dans le cytoplasme de la cellule hôte afin de détourner les fonctions cellulaires et d’assurer la survie bactérienne. Au cours de l’infection, l’immunité humorale protectrice induite est peu efficace et de courte durée. Des études récentes ont montré que Shigella, par l’intermédiaire d’effecteurs du SST3, induit l’apoptose de sous-populations lymphocytaires B et inhibe la migration des lymphocytes T. Cette migration est essentielle à la recherche d’une cellule présentatrice de l’antigène (CPA) présentant un peptide spécifique. La rencontre entre lymphocyte T et APC résulte en la formation de la synapse immunologique (SI), une plateforme de signalisation dynamique à l’interface entre ces deux cellules qui est à l’origine de l’induction de la réponse T spécifique d’un pathogène donné. La formation de la SI est dépendante du cytosquelette d’actine et du trafic vésiculaire qui permettent la relocalisation spatio-temporelle des molécules nécessaires à cette interaction cellulaire. Sachant que ces voies cellulaires sont les cibles d’effecteurs de Shigella dans les cellules épithéliales, nous avons fait l’hypothèse qu’un tel ciblage dans les lymphocytes T conduirait à l’altération de la formation de la SI et par voie de conséquence à l’activation de lymphocytes T spécifiques de Shigella. Le but de ce travail de thèse consistait donc à (1) caractériser qualitativement et quantitativement les SI formées par des cellules T préalablement infectées par Shigella et (2) en cas de différence avec les cellules non infectées, d’identifier les mécanismes moléculaires et cellulaires ainsi que les effecteurs bactériens impliqués, et d’analyser l’impact sur l’activation des cellules T. Nos résultats démontrent que le défaut de migration des cellules T infectées lié à l’action de l’effecteur SST3 IpgD réduit le nombre de conjugués formés avec les CPA. De plus, lorsque les conjugués se forment, la SI qui en résulte n’a pas les caractéristiques d’une SI mature. Nos résultats montrent que les effecteurs VirA et IpaJ induisent la fragmentation de l’appareil de Golgi et du compartiment Rab11 ce qui induit une localisation incorrecte de Lck, une protéine clé de la signalisation en aval du récepteur T (TCR). Par ailleurs, ces effecteurs participent également à l’inhibition du recyclage et de l’endocytose du TCR. Ces résultats mettent en lumière l’action coordonnée de plusieurs effecteurs du SST3 ciblant différentes voies cellulaires pour inhiber une étape-clé dans l’induction de la réponse immunitaire adaptative. En parallèle de cette étude, j’ai contribué à démontrer que les lymphocytes B et T peuvent être ciblés par Shigella via la translocation d’effecteurs du SST3 ne résultant pas en l’invasion cellulaire, définissant ainsi un nouveau paradigme pour la pathogénicité de cette bactérie. L’ensemble de ces travaux permet une meilleure compréhension des stratégies utilisées par les pathogènes pour contrecarrer la réponse immune adaptativeModulation of the host innate response during bacterial infections has been vastly documented in contrast to that of the adaptive immunity. This is the case for Shigella, the Gram negative entero-invasive bacterium responsible for bacillary dysentery, an acute rectocolitis. Shigella infection results in the invasion and inflammatory destruction of the human colonic mucosa, relying on the expression of a type three-secretion system (T3SS). Delivery of T3SS virulence effectors directly into the host cell cytoplasm results in hijacking of cellular functions that promotes bacterial survival. The humoral protective immunity elicited upon natural Shigella infection is poorly efficient and short-lasting. Recent studies have shown that Shigella promotes apoptosis of some B cell subsets and impairs T cell migration through the action of identified virulence effectors. Migratory capacities are essential for T lymphocytes to search for antigen presenting cells (APC) displaying cognate antigens. T cell-APC encountering results in the formation of a very dynamic signaling platform at the interface between the two cells, named the immunological synapse (IS), eventually leading to pathogen-specific T cell activation. IS formation is dependent on actin cytoskeleton and vesicular trafficking for spatiotemporal relocalization at the cell-cell interface of all the required molecules. Knowing that these cellular pathways are targets of Shigella T3SS effectors in intestinal epithelial cells, we hypothesized that such a targeting occurring into T lymphocytes would impact IS formation, thus preventing specific T cell activation. The aim of my thesis work was thus to quantitatively and qualitatively characterize the IS formed with Shigella-infected T lymphocytes. If impairment occurred as compared to non-infected T cells, the objectives were to decipher the underlying molecular and cellular mechanisms along with the T3SS effectors involved, as well as the impact on T cell activation. We report that Shigella, by limiting T cell migration, reduces the number of conjugates formed between T cells and APCs. When conjugates are formed, the building-up of a canonical IS is prevented by T3SS effectors-mediated targeting of actin cytoskeleton and vesicular trafficking, eventually leading to inhibition of T cell activation. In particular, besides IpgD impairing T cell scanning of APCs, two other T3SS effectors, VirA and IpaJ, are shown to induce Golgi fragmentation and disruption of Rab11 vesicular compartments, leading to mislocalization of Lck, a key protein downstream TCR signaling, and decrease of TCR recycling rate, while also participating to the down-regulation of TCR endocytosis. This study highlights the coordinated action of multiple T3SS effectors targeting diverse cellular pathways to dampen the priming of adaptive immunity. In parallel to this main study, I also contributed to demonstrate the occurrence of the translocation of Shigella effectors into B and T lymphocytes not resulting into subsequent invasion, thus leading to the establishment of a new paradigm for the pathogenicity of Shigella. Overall, this work gives rise to a more comprehensive understanding of the strategies evolved by pathogens to counteract host adaptive defenses
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Glaría, Percaz Estibaliz. "Selective effects of Liver X Receptor activation in host-bacteria interaction." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673708.
Abstract:
Macrophages exert potent microbicidal functions against pathogens; however, some intracellular bacteria have developed strategies to survive within intracellular phagolysosomes and use macrophages as a preferential niche to replicate. Liver X receptors (LXRs) are ligand- activated transcription factors of the nuclear receptor superfamily that regulate metabolic and immune functions. In this study, we explored the impact of LXR activation on host–bacteria interactions and its consequences on infection. In a murine model of orally-acquired salmonellosis, the pharmacological activation of LXRs reduced extraintestinal bacterial dissemination and attenuated the clinical signs of infection. The beneficial effects of LXR activation in the control of infection required the expression of the multifunctional protein CD38 in bone marrow-derived cells. We had previously described CD38 as a new LXR target gene that is synergistically induced by the combination of LXR agonists and inflammatory stimuli in macrophages. Here, we have identified the transcription factor C/EBPβ as an essential mediator of Cd38 induction by TNFα, IFNγ, or LPS, as well as by the combination of these inflammatory signals and an LXR agonist.
In murine macrophages, LXR activation reduced the internalisation of Salmonella Typhimurium, uropathogenic E. coli, and enteroinvasive E. coli (EIEC) but not of Listeria monocytogenes, Staphylococcus aureus, or latex microspheres. After analysing several LXR-mediated activities, we found that S. Typhimurium infection correlated with the abundance of free cholesterol in macrophages, indicating that the reduction in cellular cholesterol caused by LXR activation might mediate the inhibitory effect on bacterial entry. In primary human macrophages, LXR activation reduced the infection by S. Typhimurium but not by EIEC or S. aureus. Strikingly, LXR activation caused either no effect or a reduction in the internalisation of L. monocytogenes and latex microspheres depending on the donor. In conclusion, this work delves into the mechanisms by which LXRs modulate host interactions with bacteria. Given that the ability of many bacteria to invade host cells largely depends on initial surface contacts, modulating these events through LXR-targeting compounds opens new potential therapeutic opportunities for antibacterial drug development.
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Auma, Ann Winniefred Nangobi. "THE IMPACT OF DIRECT-ACTING ANTI-VIRAL THERAPY ON NAIVE CD4+ T CELL LYMPHOPENIA AND CELLULAR IMMUNE ACTIVATION IN HCV INFECTION AND HCV/HIV CO-INFECTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1625764728651756.