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Functions of open MHC class I molecule conformations
Vaníčková, Marie ; Poláková, Ingrid (advisor) ; Vaníková, Šárka (referee)
The major role of MHC class I molecules in adaptive system is to present antigen peptides derived from intracellular environment on the cell surface. These peptides are recognized by CD8+ T-lymphocytes and they can also interact with NK cells via trans-interaction. MHC class I molecules are composed of a heavy chain, β2-microglobulin (β2m, light chain) and peptide, forming a closed conformation. The heavy chain is non-covalently associated with the light chain and is folded into extracellular domain (α1, α2, α3 subunits), transmembrane domain and cytoplasmic domain (with conserved motifs). Upon active metabolism, the β2m and peptide may dissociate from the MHC I heavy chain what leads to the formation of open conformations of MHC I. This conformational change causes the subunit to unfold and allow its interaction with various receptors and molecules. Open conformers of MHC I may form cis-interactions with themselves creating homodimers involved in immunological functions or they can associate with different receptors on the cell surface creating heterodimers responsible for non-immunological functions. Soluble forms of free heavy chains also exist outside of the cell surface. Cis-associations are very important as they influence signaling pathways of the cell, inhibition or activation of...
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Snižují regulační T lymfocyty riziko autoimmunity indukované CD8+ T lymfocyty?
Chadimová, Tereza ; Štěpánek, Ondřej (advisor) ; Šenolt, Ladislav (referee)
5 Regulatory T cells (Tregs) are essential for the maintenance of peripheral self-tolerance and prevention of autoimmunity by suppressing the response of self-reactive CD8+ and CD4+ T cells. However, while interactions of Tregs with CD4+ T cells have been extensively studied, their effect on the self-tolerance of CD8+ T cells has not been explored in detail. The main aim of this diploma project was to provide evidence whether and how Tregs prevent autoimmunity induced by CD8+ T cells. We used an experimental mouse model of autoimmune diabetes allowing us to acutely deplete Tregs and titrate the number of self-reactive T cells, self- antigen affinity, and self-antigen doses. We found out that Tregs play an important role in the prevention of CD8+ T-cell mediated autoimmunity. Moreover, we revealed that Tregs suppress both high-affinity T cells that escape negative selection and relatively weakly self-reactive, but numerous, positively selected T cells. Tregs do so by increasing requirement for the number of self-reactive CD8+ T cells required for the autoimmunity induction. Intriguingly, presence of Tregs does not impact threshold for self-antigen. Moreover, for the first time, we showed that Tregs can suppress CD8+ T-cell-mediated autoimmunity in the absence of conventional CD4+ T cells. This means that...
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Potentiation of the biological activity of IL-2 and IL-15 in vivo
Votavová, Petra ; Kovář, Marek (advisor) ; Reiniš, Milan (referee)
5 Abstract Interleukin-2 possesses strong stimulatory activity for activated T and NK cells and thus it is an attractive molecule for immunotherapy. However, its unfavourable pharmacological properties, extremely short half-life and severe toxicities associated with high-dose IL-2 are the most serious and limiting drawbacks. Moreover, IL-2 has been also implicated in the homeostasis of T regulatory cells where it plays a decisive role as an essential growth factor of these cells. Several different approaches to improve the therapeutic potential of IL-2 have been studied. Recently described IL-2/anti-IL-2 mAb immunocomplexes which show much higher and selective biological activity in contrast with free IL-2 in vivo are probably the most promising of them. In this study, we compared the biological activity of free IL-2 with IL-2/anti-IL-2 mAb immunocomplexes in order to demonstrate their benefits over free IL-2. We also demonstrated that IL-2/anti-IL-2 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely EL4 T lymphoma and B16F10 melanoma, if administered early in tumor progression. Therefore, we justified potential use of IL-2/anti-IL-2 mAb immunocomplexes in tumor immunotherapy. We covalently conjugated IL-2 to synthetic semitelechelic polymeric carrier based...
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