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Signaling pathways in T-cell-mediated immunity
Janušová, Šárka ; Štěpánek, Ondřej (advisor) ; Hons, Miroslav (referee) ; Abramson, Jakub (referee)
The immune system provides protection of the host against pathogens, and tumor cells while maintaining a tolerance to self-tissues. T cells are important players in orchestrating the immune response. Helper T cells navigate other cells in the course of the immune response, cytotoxic T cells directly kill infected or altered cells, and regulatory T cells suppress the overt activation of above mentioned. T cells are activated via their antigen-specific T-cell receptor (TCR), but for proper activation, they need additional signals from co-stimulatory or inhibitory receptors. This double-step activation is one of the regulatory steps to prevent aberrant T-cell activation. The main part of this thesis is focused on understanding of the signal propagation and regulation of the T-cell signaling. We used a tandem affinity purification followed by mass- spectrometry analysis to describe the composition of the receptor signaling complex of TNFR- SF members, GITR and OX40. We employed the same method to analyze the signalosome of IL-17R. One of the described components of all the receptors is ABIN1. We generated ABIN1 knock-out mice that exhibited signs of autoimmunity and its T cells were hyperresponsive to various stimulation in vitro and in vivo. We reported ABIN1 as a regulator ot T-cell signaling. In the...
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Development of nanochemical tools targeting receptors in the tumor microenvironment
Blažková, Kristýna ; Konvalinka, Jan (advisor) ; Abramson, Jakub (referee) ; Bušek, Petr (referee)
Development of nanochemical tools targeting receptors in the tumor microenvironment Targeting the receptors in the tumor microenvironment is crucial for the future development of targeted therapies, precision medicine and immunotherapy of cancer. The options available now are, however, limited by the availability of specific ligands. The advances in the field strongly rely on the use of antibodies and genetic modifications of immune cells. Availability of small molecules targeting the receptors of interest would allow further development of alternative strategies as well as deepen our understanding of the underlying mechanisms of cancer development, progression and clearance. In the search for new small-molecule ligands and their use for receptor targeting, the prostate-specific membrane antigen (PSMA) and the immune receptors CD3 and CD64 were selected as model targets. The selected method - the phage display of bicyclic peptides - utilizes chemical modification of the displayed three-cysteine peptides to achieve their cyclization and formation of bicycles. The panning of a peptide library displayed on the phages and probed with PSMA revealed a reproducibly-selected amino acid sequence. Interestingly, the phage clone carrying this sequence was a specific binder of PSMA, but the synthesized peptide alone...
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Novel mechanisms regulating immune tolerance and homeostasis in the intestine
Dobeš, Jan ; Filipp, Dominik (advisor) ; Černý, Jan (referee) ; Abramson, Jakub (referee)
Immune tolerance to host own tissues and cells is the fundamental attribute of properly working immune system. The repertoire of effector T-cells, which possess randomly generated antigen-specific receptors, is during their development shaped by central immune tolerance to retain only those specificities which do not recognize self-antigens. In addition, various mechanisms of peripheral tolerance keep in check potentially self reactive cells which escaped from the protective mechanism of central tolerance. Thus, a tight regulation of tolerance, operating at several anatomical places in the host body, collectively imposes immune homeostasis and well-being of the organism. The breach of central tolerance can have far reaching consequences, as demonstrated by mutations in Autoimmune regulator gene. These mutations lead to the development of severe autoimmune disease, comprising several clinical components, gastrointestinal associated symptoms including. We have shown, that in the absence of Autoimmune regulator, the occurrence of gastrointestinal symptoms is associated with the loss of thymic- mediated central tolerance to enteric α-defensins, essential antimicrobial peptides produced by intestinal Paneth cells. The loss of tolerance leads to the escape of defensin-specific T-cells to immune periphery...
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