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The role of the interaction of LCK with CD4/CD8 coreceptors
Cesneková, Michaela ; Štěpánek, Ondřej (advisor) ; Černý, Jan (referee)
LCK kinase is an essential regulator of T-cell signalling that interacts with CD4 and CD8 coreceptors, which are crucial for T-cell development and T-cell lineage commitment. Their role, as well as the role of their interaction with LCK in the peripheral T cells, remains disputable, despite being studied for decades. This thesis aims to investigate the importance of LCK-coreceptor interaction in CD8+ T cell signalling and development and to determine the significance of the serine residues in LCK-mediated CD4 endocytosis. We used LCK variants bearing mutations of the coreceptor binding site or its catalytic domain in both mice and cell lines to solve this perplexity. First, the enzymatic activity of LCK variants was evaluated in this thesis. Second, we demonstrate that the function of CD8 is both, LCK-CD8 interaction dependent and independent. Then we examined the late stage of CD8+ T cell development, showing that the absence of the interaction has very mild consequences. It affects only the response of post- selection CD8 single-positive, but not double-positive, thymocytes to sub-optimal antigenic stimulation. Finally, we observed that CD4 with the mutation of all three intracellular serines to alanines shows similar LCK-dependency as wild type CD4. Overall, this study sheds light on the...
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Immune responses of naive and memory CD8+ T cells.
Cesneková, Michaela ; Štěpánek, Ondřej (advisor) ; Dobeš, Jan (referee)
Adaptive immune system plays a crucial role in effective pathogen clearance as well as establishment of immunological memory and its understanding is important for vaccine and drug development, besides cancer and autoimmune disease treatment. CD8+ T lymphocytes are able to efficiently kill infected cells and develop into antigen-specific memory cells, which are kept in a steady-state and demonstrate enhanced cytokine production and faster response upon reinfection, compared to naive T cells. Additionally, the pool of CD8+ memory T cells is more abundant, diversified and localizes to lymphoid as well as non-lymphoid tissues. On the other hand, proliferation rate, threshold of activation and CD28 costimulation independence are questionable. Even though the opposite was accepted for a long time, it seems that on a per cell basis, memory cells aren't superior to naive in these features and have decreased TCR sensitivity. Interestingly, in contrast to naive, memory CD8+ T cells can be activated independently of TCR, even in the absence of a cognate antigen, which emphasizes their increased sensitivity to inflammatory milieu and contribution to innate immune responses.
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Cellular and molecular mechanisms of naive T-cell priming
Kramářová, Ilona ; Musil, Jan (advisor) ; Pačes, Jan (referee)
T cell priming is a complicated signalling process involving several levels of molecular and spatiotemporal regulation. Whether TCR signalling is initiated depends on the TCR signalling threshold which is thought to be set during the T cell development in thymus by CD5 and CD6. TCR intrinsic downstream signalling ("Signal 1") involves several pathways which result in the production of the main proinflammatory transcription factors, namely NF-κB, NFAT and AP-1. Those transcription factors participate in the transcription of proinflammatory cytokines such as IL-2. The molecular interface of T cell priming involves signalling from several types of costimulatory receptors, namely CD28, CD27 and HVEM, which are allocated to the immunological synapse. A significant overlap is present between the downstream signalling networks of TCR and costimulatory molecules which amplifies the transcription of proinflammatory genes. Shortly after T cell priming, coinhibitory molecules, namely CTLA-4 and PD-1, are upregulated to deliver negative signals to tune the stimulatory signalling. The interplay between costimulatory and coinhibitory molecules represents "Signal 2" that is responsible for further progression of T cell signalling. Key words T cell priming, TCR signalling, T cell costimulation, T cell...
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