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Immunomodulation of dendritic cells by adenylate cyclase toxin from B. pertussis
Jáňová, Hana ; Adkins, Irena (advisor) ; Brdička, Tomáš (referee)
Adenylate cyclase toxin (CyaA) produced by the causative agent of whooping cough Bordetella pertussis, is a key virulence factor important for colonization of the host. CyaA targets preferentially myeloid phagocytes expressing CD11b/CD18 integrin. By elevating cytosolic cAMP in the host cells, CyaA interferes with their phagocytic, chemotactic and oxidative burst capacities. Furthermore, CyaA modulates the secretion of cytokines and the maturation state in LPS-stimulated dendritic cells (DC) by affecting the expression of costimulatory molecules. In this study, we investigated the effects of CyaA on the capacity of murine bone-marrow DC to prime CD4+ and CD8+ T cells in response to ovalbumin epitopes delivered by the CyaA-AC- toxoid, as a model antigen. Further, we examined the possible impact of CyaA on the antigen uptake and processing for MHC class I and II-restricted presentation by DC, as we previously observed a decreased T cell stimulatory capacity of CyaA-treated DC in response to soluble ovalbumin. We found out that the high levels of cAMP generated by CyaA in LPS-stimulated DC account for the decreased presentation of ovalbumin epitopes carried by CyaA-AC- toxoid on MHC class I and II molecules, thereby impairing the CD8+ and CD4+ T cell responses. Whereas CyaA did not influence the...
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Mechanisms of MHCII signaling in B lymphocytes
Kotlabová, Klára ; Brdička, Tomáš (advisor) ; Černý, Jan (referee)
During the initiation of an antigen-specific immune response, peptide fragments originating from the antigen are presented in complex with MHC class II glycoproteins (MHCgpII) on the surface of the antigen presenting cells (APC). Antigen recognition by T lymphocyte is accompanied by the formation of the molecular structure at the interface with APC called immunological synapse (IS). During this contact, signal transduction is initiated at both, T lymphocyte and APC, sides of the IS. For a long time it was thought that the only function of MHCgpII is presentation of antigen. However, later it was found that stimulation of MHCgpII led to triggering of signals contributing to decision about the further fate of APC. MHCgpII do not have any signaling motifs in their cytoplasmatic domains, and so associated molecules are necessary for the transduction of the signals. This work focuses on B lymphocytes in which the associated molecules are Ig alfa/beta, MPYS, CD19 and CD20. After the stimulation of MHCgpII these proteins mediate signaling events including activation of several families of protein kinases, phospholipase C, mobilization of calcium and activation of transcriptional factors NFAT and AP-1. In B lymphocytes, activities of these pathways may result in proliferation and differentiation but also in the...
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Non-classical MHC class II positive cell types, function and immunological context
Tušková, Liliana ; Černý, Jan (advisor) ; Brdička, Tomáš (referee)
Major histocompatibility complex class II (MHC-II) is a group of glycoproteins responsible for the presentation of exogenous antigens to T-lymphocytes. Besides the "classical" antigen presenting cells (APCs), numerous cell types were proven to be able to express MHC-II molecules either constitutively or under specific conditions. Often, the stimulus for MHC-II expression is interferon g, a pro- inflammatory cytokine typically activating promoter IV of the Class II Transactivator. Many of the non- classical MHC-II-expressing cells can serve as APCs, activating or attenuating T-cell proliferation depending on the expression of costimulatory molecules. Additional research identified some unusual functions of MHC-II molecules on non-classical cell types, including a role in prenatal development or mating. Modulation of the MHC-II expression could potentially serve many promising therapeutic purposes and new research can lead to deeper understanding of the topic. Keywords: MHC-II, ILC, basophils, TEC, antigen presentation, CIITA, IFN-gamma
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Antigen cross-presentation - mechanism and biological significance
Boháčová, Šárka ; Stříšovský, Kvido (advisor) ; Černý, Jan (referee)
iii Abstract Antigen cross-presentation is a process, when dendritic cells present exogenous antigens in context of MHC-I to CD8+ T lymphocytes. Unlike classical antigen presentation, this one goes crosswise, because exogenous antigens are otherwise usually presented on MHC-II and endogenous antigens on MHC-I glycoproteins. Molecular mechanism of cross-presentation has not been well established yet. Two major pathways are considered - vacuolar and cytosolic. In the vacuolar pathway, the internalised antigens are cleaved in the endosome by proteases and then loaded onto MHC-I. In the cytosolic pathway, the internalised antigens leave the endosome to be cleaved by the proteasome in the cytosol. They are then imported into the endoplasmic reticulum (ER) to by loaded onto MHC-I as in classical antigen presentation, or they go back into the endosome where the MHC-I loading machinery is trafficked. This process is mediated by ER proteins including those participating in ERAD, by Rab GTPases regulating vesicular transport, and by structures important for endosome maturation. Cross-presentation is important in medicine, because it ensures activation of CD8+ T lymphocytes against intracellular pathogens and cancer cells, and induction of tolerance at the...
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Epigenetic mechanisms in the interferon γ signalling pathway
Fišerová, Lenka ; Reiniš, Milan (advisor) ; Javorková, Eliška (referee)
IFNγ is an important cytosine mediating imune responses, including antitumor immunity. It can affect expression of a lot of genes, which regulate different cellular processes. In tumor cells defects in signal cascade of IFNγ and mistakes in expression of genes regulated by IFNγ, for example genes for antigen adjustment and presentation (APM) or genes for major histocompatibility complex (MHC), were observed. Epigenetic mechanisms, can play a role in regulation of expression of genes for IFNγ, as well as in regulation of expression of genes regulated by IFNγ, including the components of the IFNγ signalling pathway. In lymphocytes from tumors the ability to produce IFNγ was limited by epigenetic silencing of genes for IFNγ. In tumor cells, epigenetic silencing of genes regulated by IFNγ, of genes of the IFNγ signaling cascade, for example IRF transcription factors, and other genes regulated by IFNγ, such as genes for APM, MHC or indoldioxygenase coding genes (IDO), was demonstrated. In case of their activation by IFNγ, epigenetic changes in regulation sequences of appropriate genes, were observed. IFNγ thus can be considered as an epigenetic agent. Epigenetic modulators are able to activate expression of genes regulated by IFNγ. By this way it's possible to explain some of immunomudullatory effects...
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Mechanisms of MHCII signaling in B lymphocytes
Kotlabová, Klára ; Brdička, Tomáš (advisor) ; Černý, Jan (referee)
During the initiation of an antigen-specific immune response, peptide fragments originating from the antigen are presented in complex with MHC class II glycoproteins (MHCgpII) on the surface of the antigen presenting cells (APC). Antigen recognition by T lymphocyte is accompanied by the formation of the molecular structure at the interface with APC called immunological synapse (IS). During this contact, signal transduction is initiated at both, T lymphocyte and APC, sides of the IS. For a long time it was thought that the only function of MHCgpII is presentation of antigen. However, later it was found that stimulation of MHCgpII led to triggering of signals contributing to decision about the further fate of APC. MHCgpII do not have any signaling motifs in their cytoplasmatic domains, and so associated molecules are necessary for the transduction of the signals. This work focuses on B lymphocytes in which the associated molecules are Ig alfa/beta, MPYS, CD19 and CD20. After the stimulation of MHCgpII these proteins mediate signaling events including activation of several families of protein kinases, phospholipase C, mobilization of calcium and activation of transcriptional factors NFAT and AP-1. In B lymphocytes, activities of these pathways may result in proliferation and differentiation but also in the...
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Immunomodulation of dendritic cells by adenylate cyclase toxin from B. pertussis
Jáňová, Hana ; Brdička, Tomáš (referee) ; Adkins, Irena (advisor)
Adenylate cyclase toxin (CyaA) produced by the causative agent of whooping cough Bordetella pertussis, is a key virulence factor important for colonization of the host. CyaA targets preferentially myeloid phagocytes expressing CD11b/CD18 integrin. By elevating cytosolic cAMP in the host cells, CyaA interferes with their phagocytic, chemotactic and oxidative burst capacities. Furthermore, CyaA modulates the secretion of cytokines and the maturation state in LPS-stimulated dendritic cells (DC) by affecting the expression of costimulatory molecules. In this study, we investigated the effects of CyaA on the capacity of murine bone-marrow DC to prime CD4+ and CD8+ T cells in response to ovalbumin epitopes delivered by the CyaA-AC- toxoid, as a model antigen. Further, we examined the possible impact of CyaA on the antigen uptake and processing for MHC class I and II-restricted presentation by DC, as we previously observed a decreased T cell stimulatory capacity of CyaA-treated DC in response to soluble ovalbumin. We found out that the high levels of cAMP generated by CyaA in LPS-stimulated DC account for the decreased presentation of ovalbumin epitopes carried by CyaA-AC- toxoid on MHC class I and II molecules, thereby impairing the CD8+ and CD4+ T cell responses. Whereas CyaA did not influence the...
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