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Muindi, K. M. "Cellular lipids and immunity : characterisation of glycolipids binding the antigen presenting molecule CD1." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670089.
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Behr-Gross, Esposito-Farese Marie-Emmanuelle. "Etude de la fonction de trois marqueurs des cellules de Langerhans épidermiqueS : le granule de Birbeck, les molécules CD1 et les récepteurs pour la partie Fc des immunoglobulines G." Strasbourg 1, 1995. http://www.theses.fr/1995STR15067.
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DiSanto, James Philip. "Molecular events in human T cell activation : CD4, CD8 and the human Lyt-3 molecules /." Access full-text from WCMC, 1989. http://proquest.umi.com/pqdweb?did=745024391&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Beyers, Albertus Daniel. "Transmembrane signalling by the CD2 and CD4 molecules of T lymphocytes." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291324.
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Ferguson, Elaine D. "Molecular characterisation of ovine CD1." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/28006.
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The CD1 molecules are a family of β2-microglobulin-associated glycoproteins with strong structural homology, but weaker sequence homology, to the MHC class I antigens. In contrast to the classical class I antigens, CD1 molecules exhibit restricted tissue expression (cortical thymocytes, dendritic cells, a subset of B cells and some intestinal epithelial cells), and are nonpolymorphic. Five CD1 genes have been identified in humans , two in the mouse and several in other mammalian species (Calabi et al, 1991). CD1 expression has also been detected by immunohistological techniques in the cow, sheep and pig. The MHC class I-like structure of CD1 and the expression on classical antigen presenting cells of the immune system has pointed to a role for CD1 in antigen presentation. Indeed, evidence has been accumulating over the past few years to support this view, with several reports suggesting that CD4-8- T cells in particular may be able to recognise nonclassical presentational elements including MHC class Ib molecules such as TLa and Qa, as well as CD1. Most recently, CD1b molecules on human monocytes have been demonstrated to restrict the response of CD4-8- T cells to antigens derived from M.tuberculosis (Porcelli et al, 1992). Previous studies on the ovine CD1 family have involved the use of monoclonal antibodies to assess tissue expression and distribution, and biochemical analyses of the ovine CD1 antigens. However, no studies have been carried out to investigate ovine CD1 at the molecular level. Therefore, a human CD1C α3 probe was used to screen several sheep thymocyte cDNA libraries. The HCD1B-like cone SCD1A25 was isolated from a foetal thymocyte library. A homologous probe comprising the α3/TM/CYT domains from this clone was derived by PCR amplification and used to identify a further three ovine clones-SCD1B-42, SCD1B-52 and SCD1T10.
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Breuning, Johannes. "Molecular mechanisms of immune regulation by the receptors CD5 and CD6." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d5ac44af-e452-4561-854d-53901a78da93.
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T cells are adaptive immune cells that are essential for initiating and regulating immune responses. T cell activation is triggered by stimulation of the T cell receptor. However, sustained T cell activation requires the function of a variety of coreceptors, among them CD5 and CD6. Both receptors have been shown to have activating and inhibitory functions and modulation of CD6 function is dependent on engagement by its ligand CD166. Costimulatory signalling by CD6 involves a phosphorylation-dependent interaction between the C-terminal Y662 residue and the adaptor protein SLP-76. However, the CD6 cytoplasmic region is one of the longest in the immune system and contains phosphorylated residues which suggests that additional signalling molecules can be recruited. I identified an interaction of CD5 and CD6 with the cytoskeleton via ezrin, radixin and moesin. This interaction has an activating function on Jurkat cell activation and may play a role in receptor localisation. I also identified the adapter protein GADS as a binding partner of the CD6 Y629 residue and found evidence for bivalent binding of the GADS/SLP-76 complex to the CD6 C terminus. Costimulation by CD6 is dependent on the recruitment of this complex and mutant CD6 that cannot recruit it does not provide costimulation and may even be inhibitory in the absence of its ligand. These results suggest a model in which costimulation by CD6 depends on cooperative binding of the GADS/SLP-76 complex to two C-terminal phosphotyrosine residues in the CD6 cytoplasmic region. Binding of this complex to CD6 may enhance long-term signalling by keeping GADS/SLP-76 at the membrane or it may provide an alternative signalling pathway that enhances TCR signalling.
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Strange, Victoria Simone. "Presentation of glycolipid antigens by CD1 molecules." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497454.
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Rhind, Susan M. "Molecular analysis of ovine CD1 expression." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/30680.
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The aim of the work carried out in this thesis was to further investigate the ovine CD1 family and clarify the existing information at the cellular and molecular level. Initial studies utilised existing anti-CD1 mAbs to clarify the pattern of tissue expression of ovine CD1. Two distinct clusters of mAbs were shown to exist - the majority recognise a molecule with tissue distribution similar to CD1b whilst three mAbs, SBU-T6, CC43 and CC118 demonstrate staining of tissue macrophages, the majority of B cells and monoctyes in addition to thymocytes and dendritic cells. NH2-terminal sequencing was subsequently used to establish the antigens recognised by the mAbs SBU-T6 and CC14. This technique demonstrated that the CC14 antigen was consistent with the predicted sequence of the SCD1B42 cDNA clone whereas the SBU-T6 antigen had closest homology to the predicted amino-acid sequence of the human CD1E gene. This is particularly noteworthy as no protein product of the CD1E gene has yet been described in any species. Subsequent work attempted to isolate the gene encoding the molecule recognised by SBU-T6 using a transient expression system in which COS cells were transfected with a lymph node cDNA library contained within the vector pcDNA3. This was unsuccessful, however a sheep CD1D-like sequence was isolated from this library utilising primers based on the NH2-terminal sequence of the SBU-T6 antigen. Expression of the SCD1D gene was investigated using in situ hybridization and RT-PCR. SCD1D transcripts were demonstrated in thymus, liver, intestine, lymph node and PBLs. A further experiment investigated the expression of the SCD1B52 gene (which contains a precise deletion of exon 4). These studies have extended the knowledge of the ovine CD1 family and establish it as one of the most complex described to date. This work has demonstrated that sheep clearly express multiple CD1 isotypes as in man and rabbits in addition to the multiple CD1B-like genes reported previously.
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Huang, Bei. "Molecular interaction of the CD4 and MHC class II molecules, mapping the contact sites on CD4." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ29961.pdf.
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Huang, Bei. "Molecular interaction of the CD4 and MHC class II molecules : mapping the contact sites on CD4." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42056.
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T cells expressing CD4 recognize antigens presented by class II following the contact of CD4 with non-polymorphic regions of class II. CD4 enhances T cell activation by acting as an adhesion molecule (co-ligand function), or by bringing the CD4 associated p56$ sp{lck}$ to the vicinity of the TCR (co-receptor function).To dissect the molecular interactions which lead to CD4 function(s), wild-type (WT) and mutant CD4 molecules were expressed in the CD4-dependent 3DT52.5.8 T cell hybridomas. Results showed that multiple sites on CD4 encompassing the CDR1, the CDR3 regions of D1 and the FG loop of D2 are involved in class II interaction. The opposite face containing the CDR2 region also plays a role, either as another class II binding site, or the TCR docking site, or in another function of CD4. Co-receptor function requires a much larger site on CD4, compared to co-ligand function. A stretch of 15 amino acids which links D2 and D3 of CD4 appears to be very important for maintaining CD4 conformation, or to provide CD4 the flexibility required for its interaction with other cell surface molecules, including class II, the TCR, etc.
Crystallographic and functional studies have suggested that CD4 may dimerize, although biochemical evidence is lacking. To investigate the CD4 dimerization issue both human and mouse CD4 WT were co-expressed in 3DT52.5.8 cells. Surprisingly this led to a severe disruption of CD4 functions, although it has been shown that both human and mouse CD4 molecules are capable of interacting with human class II efficiently. As expected, co-expression of h-CD4 WT with class II-interaction-deficient CD4 mutants within the CDR1, CDR3 and the FG loop did not rescue CD4 functions. However, co-expression of CD4 WT with mutants from the CDR2 region resulted in an enhanced response. This result suggests that CDR2 mutants do not dimerize with WT molecule, therefore cannot behave as a dominant negative mutant, which is not the case for class II-interaction-deficient mutants from the CDR1, CDR3 and FG loop. Based on these results we suggest a model whereby dimerization involves, at least in part the CDR2 region. Final confirmation of this model awaits further structural data.
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Robustelli, Valentina <1986>. "Molecular characterization of unresponsiveness to BiTE CD19-CD3 therapy in adult acute lymphoblastic leukemia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9471/1/Molecular%20characterization%20of%20unresponsiveness%20to%20BiTE%20CD19-CD3%20therapy%20in%20adult%20acute%20lymphoblastic%20leukemia.pdf.
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Acute lymphoblastic leukemia is a heterogeneous disease characterized by the sequential acquisition of genetic aberrations driving the leukemic clone’s onset and maintenance. The introduction of monoclonal antibodies has both increased over all survival rates and reduced the need of intensive and prolonged chemotherapy in relapsed/refractory (R/R) ALL. Blinatumomab is a BiTE (T-cell engaging bi-specific) antibody that redirects CD3-expressing T-cells to CD19-expressing leukemic cells. To identify predictive biomarkers of response/no-response and mechanisms underlying unresponsiveness to Blinatumomab, 26 B-ALL adult patients both responder and non-responder have been molecularly characterized by gene expression profiling.
A bioinformatic analysis was performed employing the linear mixed model (LMM) in order to consider all the possible bias interfering with the results.
The LMM output allows to classify training set patients (R or NR); the following LOPO (Leave One (Patient) Out) cross validation have been performed to avoid artifacts, determined by dataset structure. 649 genes pass the LOPO filter and the genes that contribute to less than the 1% to the total variance in the first PCA component have been discarded in order to obtain a small set of significant genes (MS4A1, CSRP2, MY05C, SEMA6A, CD200, CDR1, NEGR1, SCN3A, MME, DNTT, MIR1206).
Moreover, the LMM capability of classify patients as responder or non-responder has been confirmed through its output blind application in validation set at baseline; only 1/8 patients is misclassified and additional data are needed to clarify if causes of only one patient misclassification are patient-related or structure dataset-related.
Thus, the gene signature composed by 11 genes is capable of classify as responder or non-responder to Blinatumomab treatment adult B-ALL patients at baseline and easy to use for routine diagnostics.
However, the dataset increase and deep molecular characterization (e.g. single-cell sequencing) are required to improve statistical significance and define strict associations between genomic characteristics and phenotypic features.
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Gadola, Stephan D. "Antigen presentation by MHC class I and CD1 molecules." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494507.
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Antigen presentation is the "sine qua non" of the mammalian adaptive immune stem. The assembly of MHC class 1/peptide complexes in the endoplasmic reticulum (ER) relies on the orchestrated interplay between different chaperonins, which assist MHC class I folding, and the peptide loading complex (PLC). Mutant lymphoblastoid cell lines with defective MHC class I surface expression have greatly helped the functional analysis of the PLC. The TAP transporter associated with antigen processing translocates MHC class I peptide ligands from the cytoso into the ER and is critical for successful MHC class I assembly and maturation. In the first two results chapters of this thesis I will describe the identification, clinical description and molecular and genetic analysis of a new clinical syndrome in a group of patients with dramatically reduced MHC class I surface expression. The disease in these patients could be identified as primary TAP-deficiency. The focus of the third and fourth chapter of this thesis lies on lipid antigen presentation via CDl molecules, which are known to present mycobacterial lipids to T lymphocytes. The first objective of this thesis was to generate recombinant mycobacterial lipid loaded CUl molecules as tools to measure mycobacterial lipid speclfic T cell responses in the TAP-deficient patients.
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Daniels, Brodie Belinda. "Molecular and cellular analysis of the interaction between soluble CD23 and CD11/CD18 integrins." Thesis, Nelson Mandela Metropolitan University, 2010. http://hdl.handle.net/10948/1217.
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The low affinity IgE receptor, CD23, is expressed by a wide variety of cells and cleaved from its original 45 kDa size to several smaller soluble CD23 proteins. Soluble CD23 function depends on the form of the protein and its interaction with various ligands. CD23 is believed to play an important role in regulating allergic responses and in inflammation, amongst others. β2 integrins are important in a variety of cell-adhesion reactions during immune-inflammatory mechanisms and the binding of their natural ligands generates outside-in cellular signalling, leading to cell activation. Although the binding of CD23 to β2 integrins contributes to this signalling in monocytes, the interaction site for CD23 is unknown. This study focused on the interaction of three soluble CD23 proteins with the β2 integrins CD11b/CD18 and CD11c/CD18. Differentiated HL60, THP1 and U937 monocytic cells were used to demonstrate the binding of three recombinant CD23 constructs (corresponding to 16, 25 and 33 kDa human soluble CD23) to upregulated CD11b/CD18 and CD11c/CD18. This binding was partially blocked by an antibody specific for the CD11b/CD18 αI domain, demonstrating that αI domains are involved in binding to CD23. Recombinant αI domain proteins of CD11b and CD11c were demonstrated to bind CD23 using ELISA and in surface plasmon resonance spectroscopy. The dissociation constants for CD23-CD11b/CD18 and CD23-CD11c/CD18 are comparable to other integrin ligands. This study has shown that CD23 interacts directly with the αI domains of β2 integrins and that the interaction surface likely spans the lectin domain as well as either the stalk and/or C-terminal tail of CD23. This study also looked at the effect that soluble CD23 proteins had on monocyte biology. It appears that iv sCD23 proteins have little effect on the phagocytic or chemotactic ability of monocytes, while an increase in oxidative burst was shown with the 16 kDa and 25 kDa CD23 proteins. Signalling pathways for the production of reactive oxygen species were investigated and it appears that the CD23 proteins signal mainly through the phosphoinositide-3 kinase pathway, although the mitogen activated protein kinase and Src kinase pathways may also play a role. These data suggest that sCD23 proteins induce outside-in signalling of β2 integrins and are able to change the activation state of CD11b/CD11c by stimulating oxidative burst. This needs to be further investigated by determining how the three sCD23 proteins are binding the CD11 proteins and investigating further leukocyte function and inflammatory responses by the cells.
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Woolfson, Adrian. "Natural and artificial forms of human CD1 genes." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282946.
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Hambor, John Edward. "Bifunctionality of the human CD8 molecule." Case Western Reserve University School of Graduate Studies / OhioLINK, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=case1054916413.
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Ravoet, Marie. "Cytogenetic and molecular characterization of CD3-CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome." Doctoral thesis, Universite Libre de Bruxelles, 2010. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210094.
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La variante lymphocytaire du syndrome hyperéosinophilique (L-SHE) est une pathologie extrêmement rare caractérisée par une prolifération monoclonale de lymphocytes T surproduisant l’interleukine IL-5, responsable d’une hyperéosinophilie persistante. En outre, un immunophénotype aberrant CD3−CD4+ est fréquemment observé à la surface des cellules T clonales. Cette pathologie se distingue par une lymphoprolifération chronique indolente habituellement révélée par une hyperéosinophilie sanguine et une infiltration éosinophilique des tissus cutanés. Toutefois, l’évolution vers un lymphome T observée chez certains patients suggère la présence d’un potentiel malin des cellules T. Ce modèle représente donc une rare opportunité d’identifier les changements moléculaires liés aux différentes étapes du processus transformant lymphoïde T.Dans le cadre de ce travail, nous avons cherché à établir les caractéristiques cytogénétiques et moléculaires des cellules T CD3−CD4+ d’une cohorte de patients L-SHE. L’analyse cytogénétique de cellules T CD3−CD4+ isolées au moment du diagnostic chez deux patientes (P1 et P2) a révélé la présence d’une délétion similaire 6q13-q22.1. En étudiant les stades cliniques successifs de P1 et P2, nous avons montré la persistance des cellules porteuses de la délétion 6q au cours de la progression chronique et leur prédominance lors du développement d’un lymphome T chez P1. Ces résultats suggèrent l’implication précoce et potentiellement critique de la délétion 6q dans cette pathologie lymphoproliférative T. L’analyse des dérégulations transcriptionnelles résultant de ce remaniement a montré une réduction de l’expression des gènes pro-apototiques BACH2 et PA26 dans les cellules T CD3−CD4+ de P1 et P2. En particulier, BACH2, dont l’expression diminue continuellement au cours de l’évolution de P1, jouerait un rôle oncosuppresseur dans la lymphogenèse T.
Afin d’identifier les modifications moléculaires des cellules T clonales, nous avons analysé l’expression de 95% des gènes humains dans les cellules T CD3−CD4+ de trois patients en phase chronique (P1, P2 et P3). La grande homologie des changements transcriptionnels chez les trois patients indique une altération des mêmes mécanismes moléculaires. Ainsi, un profil immunophénotypique exhaustif, validé chez trois patients supplémentaires, a pu être établi. En outre, les dérégulations des voies apoptotiques, TGFβ ou
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encore de signalisation intracellulaire altèrent l’homéostasie des cellules T CD3−CD4+ pouvant favoriser la perte de la capacité apoptotique et/ou la croissance cellulaire. Cette signature moléculaire a été étendue par l’identification de 20 microARNs dont l’expression est dérégulée dans les cellules T CD3−CD4+ d’une cohorte de 6 patients. Par ailleurs, la modification de l’expression des récepteurs impliqués dans la migration leucocytaire au cours de l’évolution de P1 pourrait expliquer l’infiltration ganglionnaire des cellules T clonales et la progression du lymphome.
La caractérisation des désordres cytogénétiques et moléculaires des cellules T CD3−CD4+ chez les patients L-SHE permettrait à terme d’identifier de nouveaux marqueurs diagnostiques et contribuer ainsi au développement de nouvelles cibles thérapeutiques dans une grande diversité de pathologies lymphoprolifératives de type Th2.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Guedes, Alves da Silva Adriana. "The Role of the CD14 molecule in equine endotoxemia." Thesis, Virginia Tech, 2012. http://hdl.handle.net/10919/76807.
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Objectives - To evaluate the effects of equine sCD14 and monoclonal antibodies (mAbs) to equine CD14 on LPS-induced TNF° expression of equine peripheral blood mononuclear cells (PBMCs). To determine serum concentrations of soluble (sCD14) in a population of horses with gastrointestinal diseases or other illnesses likely to result in endotoxemia; and identify relationships with clinical data.
Animals - Part 1; 10 healthy horses. Part 2; 55 clinical cases and 23 healthy control horses.
Procedure - Part 1; PBMCs were incubated with Escherichia coli LPS, CD14 mAb, sCD14, CD14 mAb plus E coli LPS or sCD14 plus E coli LPS. Supernatants were collected at 6 hours and assayed for tumor necrosis factor ° (TNF°) activity. Part 2; Serum sCD14 was measured at admission and then at 24 and 48 hours after admission using a bead-based multiplex assay.
Results - Part 1; Pre-incubation with CD14 mAb did not inhibit LPS-induced TNF° protein production in isolated equine monocytes. Use of sCD14 inhibited LPS-induced TNF° protein production in isolated monocytes in a concentration-dependent manner. Part 2; Serum concentration of sCD14 was positively related to duration of clinical signs (P = 0.007), respiratory rate (P=0.04) and band neutrophil count (P = 0.0002). There was no correlation between serum concentration of sCD14 and heart rate, temperature, hematocrit, lactate, white blood cell count, fibrinogen, creatinine, urea nitrogen, glucose and anion gap values. Serum sCD14 did not correlate with outcome at any time point for clinical cases.Master of Science
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Newton, Justin Philip. "Structure and function of CD31." Thesis, University of Oxford, 1997. https://ora.ox.ac.uk/objects/uuid:0183ecb4-a147-4772-a957-f53ae6ea367c.
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The regulated interaction of leukocyte with endothelium is of key importance during normal immune surveillance and leukocyte infiltration to sites of infection in the inflammatory response. This thesis is concerned with the structure and function of CD31 (platelet-endothelial cell adhesion molecule-1), one of the adhesion molecules implicated in these processes. Previous work has shown both in vivo and in vitro that CD31 is involved in the final step of leukocyte recruitment, transmigration across the endothelial monolayer. CD31 mediated adhesion is complex, since it is capable of mediating multiple adhesive interactions, both to itself (homophilic adhesion) and to other ligands (heterophilic adhesion). In order to study homophilic adhesion, an heterologous cell-protein assay was used in combination with recombinant chimeric CD31Fc fusion proteins, ICAM-3/CD31 chimeras and chimeras between human and murine CD31. These reagents located the homophilic binding site to the NH2-terminal domains 1 and 2, but also define a non-binding accessory role for the membrane proximal domains. Using site-directed mutagenesis to target all of the exposed charged residues in domain 1 and a subset of charged residues in domain 2, five residues were identified, mutations in which resulted in inhibition of homophilic adhesion. These residues map to both faces of the domain 1 immunoglobulinlike fold, suggesting that each molecule of CD31 interacts with two others. A novel zipper model of homophilic adhesion involving CD31 lateral association analogous to that seen amongst cadherins is proposed on the basis of these results. Evidence for lateral association of CD31 to form dimers was obtained from biophysical, biochemical and molecular biology techniques. These show that Cd31 exists in an equilibrium between monomeric and dimeric forms both in solution as soluble recombinant protein, and at the cell surface. In solution the affinity of the interaction was calculated to lie in the range 12-14μM. A large panel of anti-CD31 monoclonal antibodies were generated and tested for their ability to effect homophilic adhesion. Inhibitory antibodies were identified, mapping throughout the extracellular domain, away from the ligand binding site. In addition possible stimulating antibodies mapping to the membrane proximal domains were also identified. This indicates that CDS 1 may be induced to undergo conformational changes which effect homophilic adhesion, and it is proposed that these conformational changes may be linked to the ability of CD31 to form laterally associated dimers. Using the reagents described above, a screen of haematopoietic cell lines identified a novel heterophilic interaction, which was shown to be mediated by the integrin αvβ3. Proteinprotein assays were used to confirm a direct physical association between CD31 and αvβ3, and to map the integrin binding site to the third immunoglobulin-like fold of CD31. The functional significance of this interaction was assessed in neutrophil transmigration assays, in which both anti-CD31 and anti-αvβ3 antibodies were found to partially inhibit neutrophil transmigration.
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Berezkin, Kirill. "High-resolution infrared spectroscopy of the CH2 = CD2 molecule." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCK044/document.
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Dans cette thèse, nous avons considéré les spectres de la molécule CH2=CD2. Dans la partie expérimentale, nous avons enregistré des spectres infrarouges à haute résolution (~ 0,0025 cm-1) et fait une attribution complète des transitions enregistrées. Nous avons pu assigner pour la première fois un grand nombre de transitions des combinaisons peu intenses υ4+υ10, υ4+υ7 et de l'harmonique 2υ10; de bandes interdites par symétrie υ4, υ7+υ10, υ8+υ10; et des bandes «chaudes» υ7+υ10–υ10 et υ8+υ10–υ10. Pour la première fois, plus de 7000 transitions inconnues des bandes fondamentales υ2, υ3, υ6, υ7, υ8, υ10, υ12 et de l'harmonique 2υ7 ont été assignées. Sur la base de la théorie des opérateurs de perturbation et des propriétés de symétrie de la molécule étudiée, nous avons construit un hamiltonien effectif puis ajusté les énergies vibrationnelles expérimentales de quatorze états vibrationnels. De cette étude, il a résulté un écart-type pour l'ajustement d'environ (1,7–2,5)×10−4 cm−1 pour diverses régions spectrales. Nous avons également mesuré les valeurs expérimentales des intensités et des demi-largeurs et avons calculé les paramètres du moment dipolaire effectif et des coefficients d'auto-élargissement de la molécule CH2=CD2In this thesis we have considered spectra of the CH2=CD2 molecule. In the experimental part we recorded high-resolution (~ 0.0025 cm-1) infrared spectra and made full assignment of the recorded transitions. We were able to assign for the first time a lot of transitions to the weak combinations υ4+υ10, υ4+υ7 and 2υ10 overtone; forbidden due to the symmetry υ4, υ7+υ10, υ8+υ10; «hot» υ7+υ10–υ10 and υ8+υ10–υ10 bands. More than 7000 previously unknown transitions were assigned to the fundamental bands υ2, υ3, υ6, υ7, υ8, υ10, υ12 and 2υ7 overtone. On the base of operator perturbation theory and the symmetry properties of the studied molecule, we constructed an effective Hamiltonian and then fitted experimental ro-vibrational energies of fourteen vibrational states. As a result, rms-deviation of the fit was about (1.7–2.5)×10−4 cm−1 for various spectral regions. We measured also experimental values of intensities and halfwidths and calculated parameters of effective dipole moment and self-broadening coefficients of the СH2=СD2 molecule
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Bourel, Dominique. "Anticorps monoclonaux anti-cd3 : production-effets sur les lymphocytes t : role de la molecule cd3." Rennes 1, 1989. http://www.theses.fr/1989REN10021.
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MAZEROLLES, FABIENNE. "Interaction entre lymphocytes t et lymphocytes b : role des molecules lfa-1, cd2, cd4, icam-1, lfa-3 et hla de classe ii." Paris 7, 1989. http://www.theses.fr/1989PA077161.
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Le role des molecules de surface lfa-1, icam-1, cd2, lfa-3, cd4, hla de classe ii dans l'interaction entre lymphocytes t et lymphocytes b est etudie in vitro dans des tests d'activations lymphocytaires specifiques d'un antigene et restreintes par les molecules hla de classe ii. Le role de ces molecules dans l'adhesion entre lymphocytes t et b est etudie en absence d'antigene. Des peptides synthetiques, analogues de cd4 et de hla de classe ii, permettent l'analyse de l'interaction cd4 et hla de classe ii
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Sleater, Michelle Leigh. "Cellular and molecular effector mechanisms of islet allograft rejection /." Connect to full text via ProQuest. IP filtered, 2006.
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Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 151-168). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Sims, Stuart. "Molecular profiling CD8+ T-cell memory inflation." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598035.
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Infection with murine cytomegalovirus (MCMV) induces a large population of virusspecific CDS· T-cells that is maintained at a high frequency in the peripheral organs for the lifetime of the host. This striking response to MCMV is termed "memory inflation". It has also been shown that a similar response occurs after immunization with a non-repl icating adenovirus expressing a transgene. The key features which distinguish "infiating" CDS· T-cell memory responses from classica l "non-infiating" CDS· T-cell memory responses have not been fully defined. To determine the molecular signature of memory inflation I sorted antigen-specific ce lls ex vivo and compared the gene expression profiles of infiationary CDS· T-cells to those of central memory and effector CDS+ T-cells. This data showed that memory inflation has a distinct expression profile, with high expression of KLR receptors, specific chemokine receptors such as CX3CR1, transcription factors such as T-bet and Foxk1, and survival factors, such as Bcl-XL and down regu lation of inhibitory molecules such as BTLA. These inflationary cells are functional - expressing an array of cytokines, granzymes, IFNy, and TNFa, and lack transcriptional features of T-cell exhaustion. Similar features were identified in CDS· T-cells undergoing memory inflation using both the MCMV and adenovirus models. To address the turnover of these "inflationary" CDS+ T ce lls and their role in vivo, I created tetramers bound to the toxin saporin to specifically knock out inflationary cells. I found that they contribute to the control of vira l repl ication, since depletion was followed by a rise in viral load and a subsequent rebound increase in the tetrarner+ popul ation. In the final chapter I addressed the ro le of one specific cel l surface molecule, CD73, during CDS· T-cell memory. I found that although CD73 is thought to playa role in immune regu lation, CD73-1 - mice showed normal memory inflation and class ical noninflationary memory development. Overall the data in this thesis define for the first time the transcriptional profile associated with CDS· T-cell memory and show the distinct nature of this T-cell programme in vivo. Future work using further genetically modified mouse strains should allow definition of the critical molecules and pathways involved in the development of these important memory pools.
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Godec, Jernej. "Molecular Mechanisms of CD8+ T Cell Differentiation." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493424.
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CD8+ T cells are a crucial component of the adaptive immune system and are required for optimal protection from most pathogens and cancer. They function by secreting pro-inflammatory cytokines and by directly eliminating infected and malignant cells. In order to be effective, CD8+ T cells must be activated through a complex sequence of steps involving engagement of the antigen-specific T cell receptor (TCR) and other receptors, which orchestrate transcriptional, epigenetic, and metabolic changes that direct the differentiation of the responding cells. Following optimal activation, naive CD8+ T cells rapidly undergo clonal expansion and effector differentiation that enables prompt resolution of infection. Following pathogen clearance, a fraction of effector CD8+ T cells differentiate into long-lived memory CD8+ T cells that provide robust protection from re-challenge with the same microbe. However, in the context of persistent abundance of antigen and inflammation, such as in chronic infections and in cancer, the T cells instead become gradually more dysfunctional – a state known as T cell exhaustion.
The overarching goal of this thesis is to identify the cardinal features and molecular mechanisms associated with three main states in which CD8+ T cells exist: T cell memory, T cell exhaustion, and T cell effector differentiation. I used two complementary approaches to examine CD8+ T cells at the different states in vivo. First, I used classical immunology techniques including knockout mice and cellular phenotypic analyses to examine the role of cell surface molecules PD-1 and CD39 on CD8+ T cells in the context of memory and exhaustion, respectively. Secondly, I developed a novel experimental platform that enables gene perturbation in naive CD8+ T cells in vivo during their differentiation. I used this approach to systematically interrogate the transcriptional programming of activated CD8+ T cells and to identify novel regulators of effector differentiation. In a proof of concept study, I used this system to further define how the transcription factor BATF regulates CD8+ T cell activation. Additionally, I used this experimental platform to systematically interrogate the functional role of a set of ~80 transcription factors in CD8+ T cell differentiation, and identified TGIF1 as a novel regulator of this process.
The role of the co-inhibitory receptor PD-1 on CD8+ T was examined in mice using an acute respiratory infection model. PD-1 is a co-inhibitory receptor that is up-regulated on T cells following activation and recruits SHP1/2 phosphatases to directly antagonize signals through the TCR and this way inhibit the activation of T cells. It is down-regulated following the resolution of an acute infection but remains persistently expressed on CD8+ T cells in chronic infections and cancer. As such, PD-1 has been exhaustively studied for its contribution to the functional exhaustion of T cells. However, its role in acute infections remains less defined. We found that this receptor prevents over-activation and over-expansion of CD8+ T cells following initial differentiation, and is crucial for optimal differentiation of effector CD8+ T cells into functional memory cells.
Exhausted CD8+ T cells express several markers distinctive of the state. Some, like PD-1, Tim-3, and Lag-3 are well known. However, genome-wide transcriptional studies identified numerous additional genes that are differentially expressed in the exhausted state. Thus, we hypothesized that additional markers may provide characteristic features of the exhausted cell state and may function in chronic infections. We investigated one such gene – ENTPD1 – that encodes for CD39. This cell surface molecule is an ectonucleotidase that hydrolyzes extracellular ATP into ADP and AMP, which can be further broken down to immunosuppressive adenosine by CD73. In the context of the immune system, CD39 has largely been studied on CD4+ regulatory T cells, which use CD39 as a mechanism to suppress immune responses. However, surprisingly, we found that CD8+ T cells can also express CD39, but its expression is largely restricted to terminally exhausted CD8+ T cells. These cells are most dysfunctional as measured by the most limited proliferative capacity and ability to produce pro-inflammatory cytokines. We have observed this biology in both human and mouse chronic viral infections. Additional studies further demonstrated the importance of CD39 and the purinergic pathway in regulating lethal immunopathology associated with chronic LCMV infection in mice.
In addition to interrogating memory and exhaustion fates of CD8+ T cells, we also examined the initial regulatory programs involved in CD8+ T cell differentiation in vivo through gene silencing. Gene perturbation in naive T cells without prior cellular stimulation has been a continuous challenge in the field. To circumvent this limitation, we engineered a novel experimental platform that enables inducible gene knock-down in any immune cell in mice in vivo without prior manipulation of these cells. Initially, I validated this system by knocking down BATF and confirmed its essential role in CD8+ T cell responses to acute LCMV infection. Additionally, leveraging the inducible nature of the platform, I showed that BATF functions in the early stages of T cell activation but becomes dispensable once its transcriptional program is initiated.
Several other transcription factors such as T-bet, Eomes, Bcl6, and Blimp-1 have been described to regulate CD8+ T cell differentiation. However, numerous additional transcription factors may function in this process based on their rapid up-regulation following T cell activation. I used the novel platform to systematically test the functional relevance of ~80 additional transcription factors in a pooled setting. These experiments identified several novel candidate regulators of this process. We validated one such gene – Tgif1 – to confirm its role in the effector CD8+ T cell differentiation following acute LCMV infection and provide clues to the potential mechanism in which it may function.
The above projects have benefited significantly from genome-wide transcriptional datasets of cells at various states or of different genotypes that we generated or that originate from published studies. One particularly powerful approach to examine differences between different groups is gene set enrichment analysis (GSEA) that examines coordinate up- or down-regulation of sets of genes rather than assessing differential expression of specific genes. This is particularly important because changes in biological processes are often guided by relative small changes of groups of genes that act in concert rather than by a robust expression change of a single gene. This approach, however, is only informative if a relevant gene-set collection is used to analyze the data. Existing collections are largely centered around cancer biology and general biological processes but no extensive gene-set collection existed that contained information describing immune processes. Thus, we created ImmuneSigDB – the largest collection of immunology-focused gene sets to date by identifying, annotating, and reanalyzing ~400 published immunology studies. To show its broad use, we used it to examine the cross-species conservation of transcriptional responses in the immune system. We focused on analyzing transcriptional data from systemic responses to sepsis using GSEA and a novel approach, called leading edge metagene analysis. Using these approaches, we uncovered shared and species-specific biology in mouse and human transcriptional responses to sepsis.
Deciphering CD8+ T cell biology is key for conceptualizing new medical interventions that may boost their activation, memory development, and rejuvenation from functional exhaustion. We have determined that PD-1 is essential for optimal CD8+ T cell memory responses, and that BATF is a key transcription factor initiating effector T cell transcriptional programming. We also identified CD39 as a new marker of terminally exhausted CD8+ T cells and uncovered a key role for purinergic signaling in regulating lethal immunopathology in LCMV Clone 13 infection in mice. Furthermore, we developed a new experimental platform that enables systematic interrogation of gene function in any hematopoietic cell type by inducible knock-down of genes and identified TGIF1 as a novel negative regulator of CD8+ T cell responses. We have also developed a new computational resource to improve analyses of transcriptional profiles in the immune system. Together, the body of work presented in this thesis advances our knowledge of major states of CD8+ T cell biology, uncovering both novel mechanisms underlying CD8+ T cell function, as well as highlighting potential novel therapeutic targets that may be transformative in creating better vaccines, treating infections, or fighting cancer.Medical Sciences
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Fu, Jie. "Molecular Structure-Nonlinear Optical Property Relationships for a Series of Polymethine and Squaraine Molecules." Doctoral diss., University of Central Florida, 2006. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3941.
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This dissertation reports on the investigation of the relationships between molecular structure and two-photon absorption (2PA) properties for a series of polymethine and squaraine molecules. Current and emerging applications exploiting the quadratic dependence upon laser intensity, such as two-photon fluorescence imaging, three-dimensional microfabrication, optical data storage and optical limiting, have motivated researchers to find novel materials exhibiting strong 2PA. Organic materials are promising candidates because their linear and nonlinear optical properties can be optimized for applications by changing their structures through molecular engineering. Polymethine and squaraine dyes are particularly interesting because they are fluorescent and showing large 2PA. We used three independent nonlinear spectroscopic techniques (Z-scan, two-photon fluorescence and white-light continuum pump-probe spectroscopy) to obtain the 2PA spectra revealing 2PA bands, and we confirm the experimental data by comparing the results from the different methods mentioned. By systematically altering the structure of polyemthines and squaraines, we studied the effects of molecular symmetry, strength of donor terminal groups, conjugation length of the chromophore chain, polarity of solvents, and the effects of placing bridge molecules inside the chromophore chain on the 2PA properties. We also compared polymethine, squaraine, croconium and tetraon dyes with the same terminal groups to study the effects of the different additions inserted within the chromophore chain on their optical properties. Near IR absorbing squaraine dyes were experimentally observed to show extremely large 2PA cross sections ([approximately equal to] 30000GM). A simplified three-level model was used to fit the measured 2PA spectra and detailed quantum chemical calculations revealed the reasons for the squaraine to exhibit strong 2PA. In addition, two-photon excitation fluorescence anisotropy spectra were measured through multiple 2PA transitions. A theoretical model based on four-levels with two intermediate states was derived and used for analysis of the experimental data.Ph.D.
Other
Optics and Photonics
Optics
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Soares, Lanny Cristina Burlandy. "Avaliação do estado de ativação e da produção de moleculas citotoxicas por linfocitos (CD4+ e CD8+) do sangue periferico de pacientes com paracoccidioidomicose." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310976.
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Orientador: Maria Heloisa Souza Lima BlottaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-11T00:09:24Z (GMT). No. of bitstreams: 1 Soares_LannyCristinaBurlandy_D.pdf: 1993850 bytes, checksum: c3f425ae548a166847fe87f0b24ad2b0 (MD5) Previous issue date: 2008
Resumo: Em doenças causadas por microorganismos intracelulares como a tuberculose, criptococose e listeriose foi demonstrado que as células T CD8+ contribuem de forma relevante para o controle da infecção. Em trabalho anterior verificamos um aumento do número de linfócitos T CD8+ no lavado broncoalveolar de pacientes com paracoccidioidomicose (PCM) pulmonar, sugerindo um papel para estas células, cuja ação efetora se dá por meio da produção de citocinas como o IFN-? e atividade citotóxica. O presente estudo teve por objetivo verificar o estado de ativação e a produção de moléculas citotóxicas por linfócitos do sangue periférico (CD4+ e CD8+) de pacientes com PCM, indivíduos com PCM-Infecção e controles, tanto ex-vivo como in vitro, após estimulação com leveduras de P. brasiliensis. A expressão dos marcadores de ativação e moléculas citotóxicas foi avaliada por citometria de fluxo. A análise ex-vivo mostrou que, de maneira geral, os pacientes apresentam menor freqüência de células positivas para moléculas citotóxicas (granzima A, B e perforina), em relação aos indivíduos com PCM-infecção. A estimulação com leveduras de P. brasiliensis levou a um aumento discreto de células ativadas (CD69+) e uma redução na expressão de grânulos citotóxicos. A adição de IL-15 às culturas mostrou elevação da freqüência de células CD69+ apenas no grupo com PCM-infecção e controles. Já as células T CD4+ e CD8+ dos pacientes foram ativadas apenas na ausência do fungo. O efeito da adição de IL-15 na expressão dos grânulos foi pouco expressivo em relação à granzima A e B, mas maior freqüência de células CD8+perforina+ foi observada em indivíduos com PCM-infecção, em relação aos pacientes. Menor expressão do receptor para IL-15 (IL-15Ra) foi detectada em células T CD4+ de pacientes com PCM comparada ao grupo PCM-infecção e aos controles. A dosagem da granulisina sérica pela metodologia de ELISA mostrou níveis inferiores nos pacientes com PCM, comparado aos outros grupos. Além disso, os resultados mostraram uma tendência a um aumento de granulisina nos pacientes após terapia antifúngica. Em conjunto os resultados mostraram que os linfócitos de pacientes com PCM encontram-se em um estado de menor ativação, expressam menores quantidades do receptor para IL-15 e produzem níveis basais de grânulos citotóxicos (granzima A, B, perforina e granulisina). Estes fatores, ao lado de outros mecanismos que comprometem a imunidade celular, poderiam resultar em atividade citotóxica deficitária e, portanto, menor capacidade de lisar o fungo
Abstract: CD8+ T cells play a pivotal role in host defense against diseases caused by intracellular pathogens such as tuberculosis, cryptococcosis and listeriosis. In a previous study we verified an increased number of T CD8+ cells in bronchoalveolar lavage of patients with pulmonary paracoccidioidomycosis (PCM), suggesting a role for them in the local immune response. CD8+ T cells effector functions include cytokines production, mainly IFN-? and cytotoxic activity. The aims of this study were to verify the activation state as well as the production of cytotoxic molecules by peripheral blood lymphocytes (CD8+ and CD4+) from patients with PCM, individuals with PCM-infection and controls, both ex-vivo and in vitro after stimulation with P. brasiliensis yeast cells. The expression of activation and cytotoxic molecules was evaluated by flow cytometry. The ex-vivo analysis showed that, in general, the patients presented a lower frequency of granzime A, B and perforin-positive cells as compared to PCM-infection individuals. P. brasiliensis yeast cells stimulation led to a discrete increase in CD69+ cells and a reduction in cytotoxic granules expression in all groups. The addition of IL-15 to the cultures induced an increase in the frequency of CD69+ cells only in individuals with PCM-infection and controls. Differently, CD8+ and CD4+ T cells from PCM patients were activated only in the absence of fungal cells. The effect of IL-15 in granzyme A and B expression was low but a higher frequency of CD8+perforin+ was detected in individuals with PCM-infection than in patients with PCM. IL-15Ra expression was lower in CD4+ T cells from patients in relation to individuals with PCM-infection and controls. The detection of granulysin levels by ELISA showed lower levels in PCM patients than in individuals with PCM-infection and controls. Moreover, a tendency to a rise in granulysin levels was observed after antifungal therapy. Altogether the results showed that lymphocytes from PCM patients are poorly activated, express low levels of IL-15Ra and produce basal levels of cytotoxic granules (granzyme A, B, perforin and granulysin). These findings, in addition to other mechanisms that impair cellular immunity, may account to defective cytotoxic activity and consequently low capacity to kill the fungus
Doutorado
Ciencias Medicas
Doutor em Ciências Médicas
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Haque, Md Firoze. "CONTROLLED DEPOSITION OF MAGNETIC MOLECULES AND NANOPARTICLES ON ATOMICALLY FLAT GOLD SURFACES." Master's thesis, University of Central Florida, 2008. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2109.
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In this thesis I am presenting a detailed study to optimize the deposition of magnetic molecules and gold nanoparticles in atomically flat surfaces by self-assembling them from solution. Epitaxially grown and atomically flat gold surface on mica is used as substrate for this study. These surfaces have roughness of the order one tenth of a nanometer and are perfect to image molecules and nanoparticles in the 1-10 nanometers range. The purpose of these studies is to find the suitable parameters and conditions necessary to deposit a monolayer of nano-substance on chips containing gold nanowires which will eventually be used to form single electron transistors by electromigration breaking of the nanowire. Maximization of the covered surface area is crucial to optimize the yield of finding a molecule/nanoparticle near the gap formed in the nanowire after electromigration breaking. Coverage of the surface by molecules/nanoparticles mainly depends on the deposition time and concentration of the solution used for the self-assembly. Deposition of the samples under study was done for different solution concentrations and deposition times until a self-assembly monolayer covering most of the surface area is obtained. Imaging of the surfaces after deposition was done by tapping-mode AFM. Analysis of the AFM images was performed and deposition parameters (i.e. coverage or molecule/particle size distribution) were obtained. The subjects of this investigation were a molecular polyoxometalate, a single-molecule magnet and functionalized gold nanoparticles. The obtained results agree with the structure of each of the studied systems. Using the optimized deposition parameters found in this investigation, single-electron transport measurements have been carried out. Preliminary results indicate the right choice of the deposition parameters.M.S.
Department of Physics
Sciences
Physics MS
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Kotha, Jayaprakash. "Molecular mechanism of tetraspanin CD9 mediated cell motility." View the abstract Download the full-text PDF version, 2007. http://etd.utmem.edu/ABSTRACTS/2007-010-Kotha-index.html.
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Thesis (Ph.D. )--University of Tennessee Health Science Center, 2007.Title from title page screen (viewed on July 16, 2007). Research advisor: Lisa K. Jennings, Ph.D. Document formatted into pages (xiv, 150 p. : ill.). Vita. Abstract. Includes bibliographical references (p.130-150).
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Nasu, Kaoru. "Molecular characterisation and functional study of porcine CD31." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621532.
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Spruyt, Louise Landskroon. "Signal transduction by the CD2 molecule of T lymphocytes and NK cells." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314902.
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Powell, Katie Leanne. "Improving the Potency of a Melanoma Vaccine by Using a Third Co-Stimulatory Molecule." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/367230.
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Melanoma is the third most commonly diagnosed form of cancer amongst Australians and Australia has the highest incidence of melanoma in the world. At present, there are no vaccines that are approved for the treatment of melanoma. Previous research performed in the laboratory resulted in the development of a syngeneic, whole cell melanoma vaccine engineered to express high levels of the B7.1 T cell co-stimulatory molecule, in addition to using high doses of interferons to upregulate MHC Class I molecules on the surface of the vaccine cells. Results from extensive mouse trials determined that the incorporation of B7.1 into the vaccine cell model directly stimulated CD8+ T cells to effectively kill melanoma cells in CTL assays and protect mice from developing tumours following injection with live tumour cells expressing intermediate levels of B7.1, thereby replacing the requirement for CD4+ T cells. Subsequently, the vaccine technology was translated into a human allogeneic, whole cell vaccine that completed testing in 2011 on stage IV melanoma patients in a Phase I clinical trial at the Princess Alexandra Hospital, Brisbane. The purpose of this thesis was to extend this anticancer vaccine technology by investigating whether the addition of a second co-stimulatory molecule, 4-1BBL, onto the surface of the vaccine cells could replace or reduce the requirement for DCs in the stimulation and activation of CD8+ T cells targeting the cancer cells.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Science, Environment, Engineering and Technology
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Crellin, Natasha K. "Molecular phenotype of human CD4+CD25+ T regulatory cells." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30773.
Full textAbstract:
Suppression by T regulatory cells (Tregs) is a major mechanism by which the immune
system controls responses to self and innocuous foreign proteins. Although there are many
different types of Treg cells, the best characterized are those that constitutively express cellsurface
IL-2 R (CD25). The aim of this research was to; increase understanding of the
molecular phenotype of human CD4[sup +]CD25[sup +] Tregs, and was addressed using 3 different
approaches. I) Certain pathogens are known to be capable of modulating the function of
CD4[sup +]CD25[sup +] Tregs, but it was unclear i f this was via a direct or indirect mechanism. The
expression of TLR5 on human CD4[sup +]T cells was studied, and it was observed that both
CD4[sup +]CD25[sup +] effectors and CD4[sup +]CD25[sup +] Tregs express TLR5 at functionally significant
levels. Further, the TLR5 ligand flagellin is a co-stimulatory molecule for CD4[sup +]CD25[sup +] effector cells, and flagellin can increase the suppressive capacity of CD4[sup +]CD25[sup +] Tregs in the
absence o f antigen presenting cells. II) In an effort to understand the mechanism underlying
the unique functional phenotype of CD4[sup +]CD25[sup +] Tregs, including hypo-responsiveness to T
cell receptor (TCR) mediated activation and lack o f cytokine production, TCR-mediated
signaling in pure populations of ex vivo human CD4[sup +]CD25[sup +] Tregs was investigated. A
consistent defect in AKT activation in CD4[sup +]CD25[sup +] Tregs was observed, which when
reversed, abrogated CD4[sup +]CD25[sup +] Treg suppressive capacity. Ill) Clinical applications and
experimental manipulations have been hampered by the lack of a unique cell surface marker
for CD4[sup +]CD25[sup +] Tregs that is not also an activation marker for CD4[sup +]CD25[sup +] T effector cells.
Microarray analysis on single cell-derived Treg and T effector clones was performed as an
initial screen, followed by quantitative R T - PCR validation on polyclonal populations of
human CD4[sup +]CD25[sup +] Tregs. It was observed that human CD4[sup +]CD25[sup +] Tregs specificallyexpress the membrane channel protein Aquaporin 9. In summary, the research described
within is of considerable import to the study of human CD4[sup +]CD25[sup +] Tregs and their control of
immune homeostasis, and represents a significant contribution to the field of immunology.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Daigle, Tanya L. "Molecular mechanisms of CB1 cannabinoid receptor signaling and internalization /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10527.
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Willinger, Tim. "A molecular study of human CD8 T cell memory." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424830.
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Loyal, Lucie. "The molecular regulation of CD40L in CD8+ T cells." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20158.
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T Zellen können in zwei Hauptpopulationen mit unterschiedlichen Aufgaben unterschieden werden. CD4+ T Zellen exprimieren im Zuge ihrer Aktivierung CD40L, welches ein zentraler kostimulatorischer Rezeptor zur Induktion von B-Zell basierter humoraler Immunität, APC Aktivierung und einer effizienten Effektor CD8+ T Zell Entwicklung ist („Helfer-Funktion“). Im Gegensatz dazu sind die zytotoxischen CD8+ T Zellen dazu vorbestimmt, infizierte oder maligne Zellen direkt abzutöten. Jedoch wurde eine Fraktion von CD8+ T Zellen identifiziert, die nach Aktivierung CD40L exprimiert. Bisher ist nicht verstanden, wie in solchen CD8+ T Zellen a) die CD40L Expression reguliert ist, b) wann und wie die Fähigkeit CD40L zu exprimieren implementiert wird und c) was die Folgen für das Immunsystem sind.
In dieser Arbeit konnten wir zeigen, dass sowohl in CD4+ als auch in CD8+ T Zellen die CD40L Expression durch DNA-Methylierung regulatorischer Regionen des CD40LG Lokus reguliert wird. Die Demethylierung zentraler Elemente wird im Thymus implementiert, manifestiert sich mit der T-Zell Reifung und geht mit einer zunehmenden Stabilität der CD40L Expression einher. Erhöhte Expression von CD5 und NUR77 in CD40L+ CD8+ SP Thymozyten weisen auf eine positive Selektion mit hoher Affinität gegen Selbst-peptide während der Reifung im Thymus hin, welche das weitere Schicksal der CD40L exprimierenden CD8+ T Zellen beeinflusst. Naive CD40L+ CD8+ T Zellen besitzen ein anderes TCR Repertoire als CD40L- CD8+ T Zellen und reifen im Zuge ihrer Aktivierung bevorzugt zu Gedächtniszellen mit Zytokin- und Chemokinrezeptorprofilen von Tc2, Tc17 und Tc22 Zellen heran. Mit ihrem nicht-zytotoxischen Phänotyp und ihrer Genexpressionsignatur ähneln diese Zellen stark Helfer-CD4+ T Zellen und können von den klassisch zytotoxischen Tc1 und Tc17+1 Zellen durch ihre IL-6R und fehlende SLAMF7 Expression sowie der Expression von Markern die auf eine Fähigkeit in die Haut zu wandern schließen lassen, unterschieden werden.
Zusammenfassend zeigen wir hier, dass naive CD8+ T Zellen von den frühsten Entwicklungsstadien im Thymus an nicht homogen sind und die Fähigkeiten über CD40L Expression eine Helferfunktion auszuüben beziehungsweise über die Sekretion zytolytischer Moleküle Zielzellen abzutöten unabhängig vom CD4+ or CD8+ T-Zell Status sind. Zellen mit Zytokin- und Genexpressionsignaturen, die mit denen der CD8+ Helfer-T Zellen übereinstimmen, wurden von uns und anderen in Geweben (Haut, Lunge) identifiziert und tragen zu den verschiedensten autoinflammatorischen Erkrankungen bei. Diese Arbeit insinuiert daher die Notwendigkeit einer grundlegenen Neubewertung der CD8+ T Zell Fähigkeiten und Funktionen in Immunantworten.The T cell compartment consists of two major subsets with diverse assignments. CD4+ T cells express CD40L upon activation, a central co-stimulatory receptor to induce B cell mediated humoral immunity, activate APCs and prime efficient effector CD8+ T cell development (“helper function”). In contrast, cytotoxic CD8+ T cells are predetermined to kill infected or malignant cells directly. However, a fraction of CD8+ T cells expressing CD40L upon activation was identified. So far, it is not understood in CD8+ T cells a) how CD40L expression is regulated, b) when and how the ability of CD40L expression is implemented and c) what are the implications for the immune system. In this thesis, we found that CD40L expression is regulated by DNA-methylation of regulatory regions of the CD40LG locus in CD4+ as well as CD8+ T cells. The de-methylation of central elements is implemented in the thymus and increases with T cell maturation reflected by enhanced stability of CD40L expression. Elevated CD5 and NUR77 expression of CD40L+ CD8+ SP thymocytes suggests that high affine detection of self-peptides during positive selection in the thymus implements CD40L expression ability and predetermines the fate of the CD40L imprinted CD8+ T cells. CD40L+ naïve CD8+ T cells differ in their TCR repertoire from their CD40L- counterparts and preferentially mature into memory cell subsets with cytokine and chemokine receptor profiles of Tc2, Tc17 and Tc22 cells. With their non-cytotoxic phenotype and gene expression signatures, the CD40L+ memory CD8+ T cell subsets Tc2, Tc17 and Tc22 widely resemble helper CD4+ T cells and can be distinguished from classical cytotoxic Tc1 and Tc17+1 cells by their IL-6R and absent SLAMF7 expression and their skin migratory phenotype. Altogether, we demonstrate that from the earliest developmental stages in thymus onwards naive CD8+ T cells are not homogenous and the abilites to provide “CD40L based help” or “cytotoxicity mediated killing” are independent of the CD4+ or CD8+ T cell status. Cells with helper-type CD8+ T cell cytokine and gene-expression signatures were found at barrier sites (skin, lung) by us and others where they contribute to multiple autoinflammatory diseases. Therefore, this work insinuates the need to revisite CD8+ T cell capablities and function in immune responses.
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Cicmil, Milenko. "Platelet endothelial cell adhesion in molecule -1 (PECAM-1/CD31) signalling in platelets." Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270922.
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ANGENIEUX, CATHERINE. "Etude d'une banque d'adnc differentielle de cellules dendritiques. Caracterisation de la molecule cd1e." Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13087.
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Afin d'analyser le programme genetique plus specifique aux cellules dendritiques (cds), nous avons utilise une approche par la biologie moleculaire en construisant une banque d'adnc differentielle de cds humaines differenciees a partir des monocytes du sang peripherique. Nous avons cible nos travaux sur l'etude plus approfondie de deux transcrits. Le premier correspondait a la mrp4, molecule de la famille des multidrug resistance associated protein, dont la sequence complete demeurait meconnue au moment ou j'ai entrepris ce travail. Le second transcrit correspondait au cd1e. Les genes cd1 forment une famille regroupant cinq genes chez l'homme. Seules cependant quatre glycoproteines cd1a, cd1b, cd1c et cd1d avaient ete identifiees. Exprimees a la surface des cpags elles sont impliquees dans la presentation d'antigenes glycolipidiques a des lymphocytes t et nkt. Concernant le cd1e, seuls quelques transcrits avaient ete mis en evidence dans des lignees leucemiques t et l'existence d'une molecule cd1e restait a demontrer. La plus grande partie de ce travail destinee a caracteriser les molecules cd1e permet d'affirmer aujourd'hui que les cinq genes cd1 humains sont exprimes dans les cds. Cd1e se distingue des autres par sa localisation exclusivement intracellulaire. Son expression et sa localisation tres particuliere ont egalement ete retrouvees dans d'autres types de cds, incluant les cellules de langerhans de l'epiderme et les cds thymiques. Le role de cette molecule dans la presentation antigenique est suggere par sa relocalisation, dans les cds en cours de maturation, vers des endosomaux tardifs de type miic, connus pour etre impliques dans le chargement en antigenes des molecules cd1 et des molecules du cmh de classe ii. Une etude plus approfondie de la fonctionnalite des molecules cd1e, a partir des connaissances de base acquises a ce jour, permettra tres probablement de mieux comprendre la biologie de la presentation antigenique des molecules cd1.
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Martínez, Gallo Mónica. "Diagnóstico Molecular de Enfermedades de Base Genética que afectan al Sistema Inmune." Doctoral thesis, Universitat Autònoma de Barcelona, 2007. http://hdl.handle.net/10803/3805.
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Las inmunodeficiencias primarias constituyen un grupo de enfermedades de etiología diversa que tienen en común un defecto cualitativo o cuantitativo del sistema inmunitario a consecuencia del cual se alteran sus funciones, comprometiendo la defensa contra las agresiones externas. En el presente trabajo se describen las características clínicas e inmunológicas de pacientes con sospecha de inmunodeficiencia primaria o síndromes linfoproliferativos en los que se llevó a cabo el diagnóstico molecular. Se evaluó la capacidad oxidativa de granulocitos en una paciente que había sufrido infecciones de repetición por bacterias catalasa positiva, observándose la falta de producción de superóxido. El estudio genético de la subunidad p47-phox de la NADPH-oxidasa mostró una deleción del dinucleótido GT al inicio del exón 2 del gen NCF1, siendo diagnosticada de Enfermedad Granulomatosa Crónica.
Se estudió el caso de un paciente con infecciones de repetición durante el periodo neonatal y una severa linfopenia T y B. Se realizó el diagnóstico de Déficit de ADA a través de un ensayo de actividad enzimática. Posteriormente, se realizó un trasplante alogénico de donante emparentado haploidéntico, con exitosa recuperación del sistema inmunológico.
Analizamos un paciente varón con sospecha clínica de inmunodeficiencia humoral, con un número disminuido de células B e hipogammaglobulinemia. Por métodos bioquímicos se puso de manifiesto la falta de expresión de la proteína Btk. El análisis genético del gen BTK, mostró una nueva mutación (Q103X) que afectaba al dominio PH de la Btk, siendo diagnosticado de XLA con una correlación completa entre el genotipo, expresión proteica y fenotipo clínico.
En los casos estudiados con Síndrome de Hiper IgM se descartó que fuesen formas debidas a alteraciones en las moléculas principales del eje CD40-CD40L. Encontramos ausente la población de células B memoria, analizando la expresión de IgM y CD27 en células B CD20+. Se realizó el estudio genético del gen AID, así como de las regiones constantes de las cadenas pesadas de las inmunoglobulinas, sin encontrar alteraciones. Estas características nos indican que el defecto en el cambio de isotipo podría encontrarse en este proceso tras la rotura del DNA y nos permite caracterizarlos dentro del grupo HIGM4.
Se analizan los rasgos clínicos, inmunológicos y genéticos de once pacientes con sospecha de ALPS. Hemos descrito dos familias con mutaciones que afectan al residuo 234 de la proteína FAS, las cuales se correlacionan con una apoptosis vía Fas disminuida, con la presencia de células DNT y con una penetrancia clínica variable, lo que nos permite definirlas como ALPS tipo Ia. El resto de los pacientes, sin mutaciones en Fas, con alteraciones funcionales en la apoptosis vía Fas se clasifican en el grupo de ALPS III.
Por último, se ha estudiado una población doble positiva (DP) en un paciente con patología respiratoria. Las características de la población indican que fenotípicamente se trata de una población T CD3+CD4+CD8+αβ, que funcionalmente pertenece a la estirpe de células T colaboradoras CD4. La expresión de CD103 y de CCR6 en la población DP, y su presencia en el órgano diana de la enfermedad, justifican su tropismo a mucosa pulmonar y relacionan dicha población con la patología respiratoria. Aunque el paciente no presentó rasgos de malignidad, el análisis del repertorio Vβ mostró reordenamientos clonales, que junto a las alteraciones cromosómicas sugerirían un estado preleucémico, que requeriría alteraciones adicionales para desarrollar un proceso neoplásico franco.
Los resultados de esta Tesis muestran que la complejidad de las patologías que afectan al sistema inmunológico, requiere técnicas cada vez más específicas para determinar los defectos responsables de un fenotipo concreto. El estudio genético, molecular y funcional sistemático de estas enfermedades permite diagnosticar y clasificar entidades ya descritas, así como abordar el diagnóstico de nuevas patologías.
Although primary immunodeficiency disorders are relatively rare, intensive investigation of these disorders has yielded great understanding of basic immunologic mechanisms in host defense, inflammation, and autoimmunity. In this thesis we described the clinical and immunological features of patients with suspected of primary immunodeficiency disorders or lymphoproliferative syndromes.
We assessed the NADPH oxidase activity in a patient with catalase-positive microbial infections, the results showed a deficiency in superoxide production. The mutation analysis of the structural component p47-phox revealed a GT deletion in a GTGT repeat sequence at the beginning of exon 2 of NCF1, with the subsequent diagnosis of Chronic granulomatous disease.
We studied a patient with overwhelming infections within the first year of life and severely reduced counts of peripheral T and B cells. The patient had no detectable ADA activity associated with severe metabolic disturbances. He was treated with histocompatible bone marrow transplantation from haploidentical related donor, with successful recovery of the immunological system.
We analyzed a patient with recurrent pneumonia characterized by low to undetectable levels of B cells and serum immunoglobulins. The expression of BTK protein was completely abolished in this patient evaluated by Western-blot. We described a novel mutation (Q103X) resulting in a premature stop codon, which encodes a deleterious truncated protein. We found a complete phenotype/genotype correlation in our XLA patient.
We studied two patients characterized by very low IgG and IgA levels and normal or increased IgM diagnostic of Hyper-IgM syndrome. The CD154/CD40 pathway was analyzed discarding alterations. Mature class-switched CD27+IgM- memory B cells were profoundly diminished. The molecular analysis of AID and immunoglobulin heavy chains revealed no mutations. Although the molecular basis of these cases is still unknown, their clinical and immunologic findings have been well characterized.
Several patients with clinical and immunological features of ALPS were analyzed. The molecular analysis of Fas gene showed two families with heterozygous mutations affecting different positions of 234 codon associated with increased αβ-DNT cells and defective in vitro receptor-mediated lymphocyte apoptosis. Other patients in this study with a clinical syndrome of ALPS have been found to have a normal FAS gene with impaired in vitro apoptosis and were diagnosed of ALPS IIII.
We report an adult male who had recurrent episodes of pulmonary infiltrates with severe acute respiratory failure over a period of ten years. Clinical and pathological characteristics revealed BOOP that responded dramatically to Prednisone and other immunosuppressor treatments. A high proportion of circulating double positive T (DP-T) cells was detected in peripheral blood and in bronchoalveolar lavage, the entire DP-T cell subset were to TCRαβ CD3+CD4+CD8αβ+ lymphocytes. The CD103 and CCR6 expression in DP-T cells could explain their tropism to lung tissue. The TCRV-β chain analysis indicated clonal rearrangement and cytogenetic studies displayed chromosomic alterations that were similar to clonal proliferation observed in ataxia-telangiectasia and T-prolymphocytic leukemia. These findings suggest a smouldering form, in which the first sign is an organizing pneumonia that needs a constant corticoid treatment.
Our results show that the complexity of pathologies that affect the immune system demand more specific techniques to determine the defects of a specific phenotype. The genetic, molecular and functional systematic analysis of these diseases allows a proper diagnosis and classification of known entities, and screen for undescribed pathologies.
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MacHugh, Niall. "The biochemistry, molecular biology, and cellular expression of bovine CD8." Thesis, Brunel University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336659.
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He, Qi. "Molecular analysis of the CD2 surface glycoprotein of T lymphocytes." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236171.
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MacLachlan, Bruce. "Molecular characterisation of CD4+ T cell responses to tumour antigens." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/98044/.
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Background – Colorectal cancer (CRC) is the second most common cause of cancer death. CD4+ T cells play an important role in anti-tumour immunity by promoting immune processes that can mediate tumour inhibition. CD4+ immunity to tumours, however, is not able to prevent tumour outgrowth. It is hypothesised that tumour outgrowth can occur due to weak recognition of tumour-derived epitopes by tumour-reactive T cell receptors (TCRs) and due to negative reg-ulation by inhibitory T cell molecules. In this study, CD4+ T cell responses to the oncofoetal antigen 5T4 are studied at the molecular level. The function of the co-inhibitory molecule LAG-3 is described biophysically and monoclonal antibodies which recognise LAG-3 were devel-oped. Results – Three 5T4-reactive CD4+ T cell clones were shown to recognise 5T4-derived pep-tides restricted to HLA-DR1. Each clone was sensitive to antigen and produced TH1 cytokines despite exhibiting weak recognition of cognate antigen. Subsequently, the structural character-istics of a 5T4-derived peptide epitope was described through x-ray crystallography which revealed insights into MHC-II presentation of peptides. Cell expressed LAG-3 was shown to interact with MHC-II at the cell surface and was characterised at the protein level using surface plasmon resonance (SPR) where LAG-3 bound MHC-II via an intermediate affinity interaction. Thirdly, through the immunisation of mice, anti-LAG-3 antibodies were cloned and character-ised in terms of their specificity and function. Conclusions – These studies demonstrate how tumour-specific CD4+ T cells can produce immune-stimulatory molecules in vitro yet exhibit weak engagement of cognate antigen. It is shown that peptide flanking residues of HLA-DR1 presented epitopes can contribute to peptide anchoring as well as form structural features that may influence TCR binding. It is shown that LAG-3 binds MHC-II at higher affinity than CD4 with implications in its inhibitory function. Finally, specific antibodies that bind LAG-3 have been characterised with potential for thera-peutic development.
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Gordon, Colin B. "Molecular genetics of the cdc 22 gene of Schizosaccharomyces pombe." Thesis, University of Edinburgh, 1985. http://hdl.handle.net/1842/14920.
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De, Simone Marco <1975>. "Molecular characterization of human CD4+ IL-10-producing regulatory cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6520/1/De_Simone_Marco_tesi.pdf.
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Previous studies in the group led to the identification of CD4+FOXP3- cells with regulatory functions in human blood that coproduce IL-10 and IFN-gamma. These cells do not belong to the Treg cell lineage since they are Foxp3- but they show some similarities with Th1 cells since they express CCR5, T-bet and produce high levels of IFN-gamma. Thus, they share relevant characteristics with both T regulatory type I cells (Tr1) and Th1 cells and we called them Th1-10 cells.
In this study we presented a molecular characterization of Th1-10 cells that includes a gene expression and a microRNA profiling and performed functional studies to assess Th1-10 cells regulatory properties. We demonstrated that Th1-10 cells have a high regulatory potential being able to block the proliferation of activated CD4 naïve T cells to a similar extent as conventional Treg cells, and that this suppression capacity is at least partially mediated by secreted IL10.
We showed also that Th1-10 cells are closely related to Th1 effector memory cells and express genes involved in cytotoxicity. In particular, they express the transcription factor EOMES and the cytotoxic effector molecules GZMA and GZMK, and they release cytotoxic granules upon stimulation. Moreover, we found that Eomes regulates cytotoxic functions in CD4+ T cells.
We demonstrated that miR-92a, selectively downregulated in Th1-10 cells, directly targets the 3’UTR of EOMES.and this finding identifies miR-92a as a possible mediator of Th1-10 cytotoxicity.
Th1-10 cells retain some proliferative capacity when sorted ex vivo and activated in vitro via their TCR, and this effect is markedly enhanced by IL-15, which also had a pro-survival effect on Th-10 cells.
Thus, in contrast to conventional cytotoxic T cells, Th1-10 cells have cytotoxic and regulatory functions and are not terminally differentiated, since they retain proliferative capacity.
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De, Simone Marco <1975>. "Molecular characterization of human CD4+ IL-10-producing regulatory cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6520/.
Full textAbstract:
Previous studies in the group led to the identification of CD4+FOXP3- cells with regulatory functions in human blood that coproduce IL-10 and IFN-gamma. These cells do not belong to the Treg cell lineage since they are Foxp3- but they show some similarities with Th1 cells since they express CCR5, T-bet and produce high levels of IFN-gamma. Thus, they share relevant characteristics with both T regulatory type I cells (Tr1) and Th1 cells and we called them Th1-10 cells.
In this study we presented a molecular characterization of Th1-10 cells that includes a gene expression and a microRNA profiling and performed functional studies to assess Th1-10 cells regulatory properties. We demonstrated that Th1-10 cells have a high regulatory potential being able to block the proliferation of activated CD4 naïve T cells to a similar extent as conventional Treg cells, and that this suppression capacity is at least partially mediated by secreted IL10.
We showed also that Th1-10 cells are closely related to Th1 effector memory cells and express genes involved in cytotoxicity. In particular, they express the transcription factor EOMES and the cytotoxic effector molecules GZMA and GZMK, and they release cytotoxic granules upon stimulation. Moreover, we found that Eomes regulates cytotoxic functions in CD4+ T cells.
We demonstrated that miR-92a, selectively downregulated in Th1-10 cells, directly targets the 3’UTR of EOMES.and this finding identifies miR-92a as a possible mediator of Th1-10 cytotoxicity.
Th1-10 cells retain some proliferative capacity when sorted ex vivo and activated in vitro via their TCR, and this effect is markedly enhanced by IL-15, which also had a pro-survival effect on Th-10 cells.
Thus, in contrast to conventional cytotoxic T cells, Th1-10 cells have cytotoxic and regulatory functions and are not terminally differentiated, since they retain proliferative capacity.
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HUBERT-HADDAD, PASCALE. "Transduction du signal d'activation induit par la stimulation des molecules cd3 ou cd2 du lymphocyte t : effet de la glycoproteine d'enveloppe gp120 du virus de l'immunodeficience humaine de type 1." Paris 6, 1996. http://www.theses.fr/1996PA066587.
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Les lymphocytes t peuvent etre actives in vitro par un anticorps specifique du complexe cd3-recepteur t, ou par un couple d'anticorps reconnaissant la molecule cd2. Le signal declenche par le cd2 semble etre similaire a celui induit par cd3, et necessite l'expression du cd3 a la surface de la cellule. Nous avons montre au cours de ce travail que le cd2 induit aussi un signal qui lui est propre. En effet, dans la lignee t jurkat, le cd2 induit la tyrosine phosphorylation d'une proteine de 62 kda associee a la plc-1, independamment de l'expression du cd3. Cette p62 semble etre identique a la p62 liee a la proteine gap. A l'inverse, le cd3 induit la tyrosine phosphrylation de la tyrosine kinase zap-70 et des chaines du cd3, contrairement au cd2. Cependant, la plc-1 est activee de facon identique par cd3 et cd2, vraisemblablement par la tyrosine kinase p56lck. La plc-1 s'associe a zap-70 apres stimulation du cd3, et a la p62 apres stimulation du cd2, suggerant que ces deux molecules pourraient jouer le role de proteines d'ancrage specifiques de chaque voie. De meme, le clone t cd4+ humain p28 cultive avec la gp120 du v. I. H. -1 presente une inhibition des tyrosine phosphorylations apres stimulation du cd3, mais pas du cd2. L'inhibition de la voie cd3 semble liee a la rupture des interactions entre les complexes cd4-p56lck et cd3-recepteur t, et pourrait etre due a un signal negatif delivre par la gp120 via le cd4-p56lck. La gp120 cree un etat similaire a l'anergie, en induisant une diminution de l'activite de la p56lck et de zap-70, et une augmentation de celle de la p59fyn. En outre, la phosphorylation des chaines du cd3 induite par le cd2 est inhibee en presence de gp120, suggerant qu'elle n'est pas indispensable au signal cd2.
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Martins, Soraia Alexandra Araújo. "CD81 interacting proteins." Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/16139.
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Mestrado em Biomedicina MolecularFertilization is a multistep and complex process culminating in the merge of gamete membranes, cytoplasmic unity and fusion of genome. CD81 is a tetraspanin protein that participates in sperm-oocyte interaction, being present at the oocyte surface. CD81 has also been implicated in other biological processes, however its specific function and molecular mechanisms of action remain to be elucidated. The interaction between CD81 and its binding partner proteins may underlie the CD81 involvement in a variety of cellular processes and modulate CD81/interactors specific functions. Interestingly, in a Yeast two Hybrid system previously performed in our lab, CD81 has emerged as a putative interactor of the Amyloid Precursor Protein (APP). In the work here described, bioinformatics analyses of CD81 interacting proteins were performed and the retrieved information used to construct a protein-protein interaction network, as well as to perform Gene Ontology enrichment analyses. CD81 expression was further evaluated in CHO, GC-1 and SH-SY5Y cell lines, and in human sperm cells. Additionally, its subcellular localization was analyzed in sperm cells and in the neuronal-like SH-SY5Y cell line. Subsequently, coimmunoprecipitation assays were performed in CHO and SH-SY5Y cells to attempt to prove the physical interaction between CD81 and APP. A functional interaction between these two proteins was accessed thought the analyses of the effects of CD81 overexpression on APP levels. A co-localization analysis of CD81 and some interactors proteins retrieved from the bioinformatics analyses, such as APP, AKT1 and cytoskeleton-related proteins, was also performed in sperm cells and in SH-SY5Y cells. The effects of CD81 in cytoskeleton remodeling was evaluated in SH-SY5Y cells through monitoring the effects of CD81 overexpression in actin and tubulin levels, and analyzing the colocalization between overexpressed CD81 and F-actin. Our results showed that CD81 is expressed in all cell lines tested, and also provided the first evidence of the presence of CD81 in human sperm cells. CD81 immunoreactivity was predominantly detected in the sperm head, including the acrosome membrane, and in the midpiece, where it co-localized with APP, as well as in the post-acrosomal region. Furthermore, CD81 co-localizes with APP in the plasma membrane and in cellular projections in SH-SY5Y cells, where CD81 overexpression has an influence on APP levels, also visible in CHO cells. The analysis of CD81 interacting proteins such as AKT1 and cytoskeletonrelated proteins showed that CD81 is involved in a variety of pathways that may underlie cytoskeleton remodeling events, related to processes such as sperm motility, cell migration and neuritogenesis. These results deepen our understanding on the functions of CD81 and some of its interactors in sperm and neuronal cells.
A fecundação é um processo complexo e faseado que culmina na fusão celular das membranas dos gametas, do citoplasma e do genoma. A CD81 é uma proteína tetraspanina que participa na interacção espermatozóide-oócito, estando presente na superfície do oócito. A CD81 também tem sido associada a outros processos biológicos, contudo a sua função específica e os seus mecanismos de acção não estão elucidados. A ligação entre a CD81 e as suas proteínas interactoras fundamenta o envolvimento da CD81 numa variedade de processos celulares e funções específicas. O desenvolvimento de um sistema de Dois Híbrido em Leveduras, anteriormente realizado no nosso laboratório, mostrou que a CD81 potencialmente interage com a Proteína Percursora de Amilóide (PPA). No presente trabalho, foi realizada a análise bioinformática das proteínas interactoras da CD81. A informação obtida permitiu a construção de uma rede de interações proteína-proteína, bem como a análise de enrequecimento de Ontologia de Genes. Adicionalmente, a expressão da CD81 foi avaliada nas linhas celulares CHO, GC-1 e SH-SY5Y e em espermatozóides humanos. A sua localização subcelular foi também analisada em espermatozóides humanos e na linha de neuroblastoma SH-SY5Y. Foram ainda realizados ensaios de coimunoprecipitacão nas linhas celulares CHO e SH-SY5Y, com a tentativa de provar a intercação física entre a CD81 e a PPA. A interação funcional entre estas duas proteínas foi estudada através da análise do efeito da sobreexpressão da CD81 nos níveis de PPA. Foram também realizados estudos de colocalização entre a CD81 e algumas proteínas interactoras, nos espermatozóides humanos e na linha celular SH-SY5Y. Os interatores analisados, PPA, AKT1 e proteínas relacionadas com o citoesqueleto, foram obtidos da análise bioinformática previamente realizada. O efeito da CD81 na remodelação do citoesqueleto foi avaliado através da monitorização dos efeitos da sobre-expressão da CD81 nos níveis de actina e tubulina, bem como através da análise da colocalização entre a CD81 sobre-expressa e a F-actina. Os nossos resultados mostram que a CD81 está expressa em todas as linhas celulares testadas, providenciando a primeira evidência da presença da CD81 em espermatozóides humanos. A marcação da CD81 foi predominantemente detectada na cabeça do espermatozóde e na peça intermédia, onde colocaliza com a PPA, bem como na região pós-acrossómica. Em adição, a CD81 colocaliza com a PPA na membrana plasmática e nas projecções celulares das células SH-SY5Y, onde a sobre-expressão da CD81 influencia os níveis de PPA, efeito também observado nas células CHO. A análise de proteínas interactoras da CD81, como a AKT1 e proteínas relacionadas com o citoesqueleto, evidenciou que a CD81 está envolvida na remodelação do citoesqueleto, nomeadamente na motilidade dos espermatozóides, na migração celular e na neuritogénese. Estes resultados permitiram aprofundar o conhecimento das funções da CD81 e de alguns dos seus interactores, em espermatozóides e em células neuronais.
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Coudronnière, Nolwenn. "Régulation du cycle de réplication du virus de l'immunodéficience humaine de type (vih-1) par des signaux transmis par la molécule cd4." Montpellier 1, 1998. http://www.theses.fr/1998MON1T008.
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Martin, Laurent. "Etude des autoanticorps anti-cd4 au cours de l'infection par le virus de l'immunodeficience humaine : production de la molecule cd4 recombinante soluble et utilisation de deux techniques immunoenzymatiques." Lille 2, 1993. http://www.theses.fr/1993LIL2M184.
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Xiang, Guoqing. "Signaling Through Homomeric and Heteromeric Cannabinoid CB1 receptors." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5683.
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Cannabis (Marijuana) has multiple effects on the human body, such as analgesia, euphoria and memory impairment. Delta-9 tetrahydrocannabinol (D9-THC), the active ingredient in cannabis, binds to cannabinoid receptors, seven-transmembrane G protein-coupled receptors (GPCRs) that mediate a variety of physiological functions. GPCRs were believed to function only in homomeric forms, however, recent findings show that different GPCRs can also form heteromeric complexes that may expand their signaling properties. In this study, we focused on Cannabinoid CB1 receptor (CB1R) heteromers with the mu-opioid receptor (MOR) and the Dopamine type 2 receptor (D2R), respectively. We utilized a variety of techniques, such as the calcium mobilization assay, a luciferase complementation assay and an electrophysiology assay to study the pharmacology of the CB1R-MOR and CB1R-D2R heteromers. Our data demonstrate that co-expression of CB1R enhances the Gi signaling through MOR and inhibits the beta-arrestin recruitment to MOR. We also show that co-application of CB1R ligands can further accentuate the MOR signaling modulation. Co-expression of a CB1R transmembrane domain 5 (TM5), but not a TM1, mini-gene abrogated the signaling change suggesting that it is likely due to heteromerization of MOR and CB1R. Utilizing this herteromeric signaling could provide a novel therapeutic approach that may yield potent analgesic effects with reduced side effects. We have also found that CB1R switched its signaling specificity from Gi to Gs upon its heteromerizaiton with D2R. In conclusion, our data show that CB1R expands its signaling repertory and modulates the partner receptor signaling upon heteromerization.
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Hirji, Nadir. "The expression and function of a novel CD8 molecule on alveolar macrophages and mast cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0008/NQ59967.pdf.
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