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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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Role of CD8- and CD4-Lck interactions in the signaling and development of T cells.
Horková, Veronika ; Štěpánek, Ondřej (advisor) ; Černý, Jan (referee) ; Hons, Miroslav (referee)
Adaptive immune response plays a key role in maintaining homeostasis of the organism. T cells use an immense repertoire of T-cell receptors (TCRs) to discriminate between self and foreign antigens with very high sensitivity. Although we have many clues outlining how an ideal TCR repertoire is selected, and a good understanding of the TCR signaling machinery, there are still some key aspects of these processes that remain controversial. The objective of this thesis is to extend our knowledge of the very proximal events of TCR signaling, with special focus on interaction of TCR coreceptors with lymphocyte-specific kinase LCK. Coreceptor-LCK interaction has been described to regulate several aspects of T- cell development and response. We observed dynamic change of this interaction in course of T-cell development. Interestingly, CD4 and CD8 coreceptors displayed differential dynamics of interaction with LCK. Our data suggest that such disparity in coreceptor- LCK interaction leads to selection of more self-reactive TCR repertoire in CD8+ T cells. Moreover, when the highly self-reactive CD8+ T cells get to the periphery, the homeostatic signals drive their differentiation towards a more tolerogenic memory-like phenotype. To finally resolve the role of coreceptor-LCK interaction in the T-cell...
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