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Heterogeneity of antigen-presenting cells in the thymus and its relevance for the establishment of central tolerance
Sýkora, Vojtěch ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
The crucial function of the thymus is the establishment of central tolerance. In this process, developing T-cells are tested for their self-reactivity, since self-reactive T-cells might cause the autoimmunity if they would escape from the thymus to the periphery. Many thymic antigen-presenting cells are essential for establishment of central tolerance. Their role is to present self-antigens to the developing T-cells. Such presentation is capable to reveal the self-reactive potential of T-cells which can be then directly removed or deviated into suppressive T-regulatory cells. In the last several years, a high level of heterogeneity has been described among the thymic antigen-presenting cells and the molecular mechanisms that govern their functions towards enforcement of tolerance began to be uncovered. This thesis summarises recent knowledge in the field of heterogeneity of the thymic antigen-presenting cells and its relevance for establishment of the central tolerance, with the major focus on conventional dendritic cells and post-AIRE medullary thymic epithelial cells. This thesis also outlines recent advances in understanding of functional mechanisms and regulations of maturation of the antigen-presenting cells.
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CX3CR1+ migratory dendritic cells in the mechanisms of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Display of thousands of self-antigens in the thymus is fundamental for the establishment of central tolerance as its failure can lead to the development of autoimmunity. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) constitute essential populations of antigen presenting cells (APCs) which present these self-antigens to developing T cells. While mTECs produce and present antigens in self-autonomous manner, DCs can hijack mTEC-derived antigens by the process of cooperative antigen transfer (CAT). It is well found that CAT is essential for working central tolerance, however, the overall heterogeneity of thymic APCs participating in CAT remains unclear. Using transgenic mouse models and multicolor flow cytometry analysis, we determined that APCs involved in CAT are exclusively of CD11c+ phenotype. Within these cells, we identified previously unrecognized CX3CR1+ subset of migratory DCs (mDCs) exhibiting monocyte/macrophage markers. These CX3CR1+ mDCs are more efficient in CAT than their CX3CR1- counterparts and reveal robust antigen presenting properties with the capability to present CAT-acquired antigen. Genetic ablation of CX3CR1+ mDCs resulted in increased cellularity of CD8+ and CD4+ thymocytes, indicating importance of this mDC subset for negative selection of...
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Defensins and autoimmunity: emerging alpha-defensin based model to study mechanisms underpinning autoimmune processes
Neuwirth, Aleš ; Filipp, Dominik (advisor) ; Černý, Jan (referee) ; Michálek, Jaroslav (referee)
The process of immune "self-nonself discrimination" is of utmost importance for the survival of all species as the biodestructive force of immune system can be directed towards the host as much as to pathogens. Thus, to shift this balance towards the latter, T cells bearing self- recognizing receptors are removed in the thymus (central tolerance) or their reactivity is harnessed through various additional mechanisms in periphery (peripheral tolerance). If the selfreactive T cells are not deleted and persist in the body, the regulation of self-tolerance can be breached, leading to the onset of autoimmunity. Presented thesis revolved around α-defensins, very effective bactericidal peptides that represent an important part of humoral innate immunity. There are two types of α-defensins: myeloid, expressed predominantly in neutrophils, and enteric, synthesized by intestinal Paneth cells. Data presented inhere are first to characterized the involvement of α-defensin- expressing cells in two types of autoimmune diseases, insulin-dependent diabetes mellitus (T1D) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The former relates to the identification of transcriptionally activated myeloid α-defensin- expressing eosinophils present in the thymus of diabetes prone rat. In...
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CX3CR1+ migratory dendritic cells in the mechanisms of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Display of thousands of self-antigens in the thymus is fundamental for the establishment of central tolerance as its failure can lead to the development of autoimmunity. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) constitute essential populations of antigen presenting cells (APCs) which present these self-antigens to developing T cells. While mTECs produce and present antigens in self-autonomous manner, DCs can hijack mTEC-derived antigens by the process of cooperative antigen transfer (CAT). It is well found that CAT is essential for working central tolerance, however, the overall heterogeneity of thymic APCs participating in CAT remains unclear. Using transgenic mouse models and multicolor flow cytometry analysis, we determined that APCs involved in CAT are exclusively of CD11c+ phenotype. Within these cells, we identified previously unrecognized CX3CR1+ subset of migratory DCs (mDCs) exhibiting monocyte/macrophage markers. These CX3CR1+ mDCs are more efficient in CAT than their CX3CR1- counterparts and reveal robust antigen presenting properties with the capability to present CAT-acquired antigen. Genetic ablation of CX3CR1+ mDCs resulted in increased cellularity of CD8+ and CD4+ thymocytes, indicating importance of this mDC subset for negative selection of...
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The role of NF-kappa B signaling in establishment of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Ce trál í tolera e, která je usta ove a v th u, výz a ě redukuje repertoár reaktiv í h T l fo tů a tí u ožňuje před házet rozvoji autoi u it í h o e o ě í. ez t ý Autoi u it í regulá Aire , který je e pri ova ý ikát í i edulár í i epiteliál í i uňka i řídí pro iskuit í ge ovou e presi tisí ů tkáňově spe ifi ký h a tige ů, která je zásad í pro úči ou egativ í selek reaktiv í h T l fo tů regulač í h l fo tů. Výzku posled í h dvou dekád sta ove í e trál í tolera e. této prá i předkládá ejdůležitější poz atk dokládají í její klíčovou roli ve vývoji u ěk pří é regula i ge ové e které hovoří ve prospě h edo e ě é skuteč ost , že hlav í regulátore pro esů podílejí í h se a vý , udržová í a fu k i e trál í tolera e Klíčová slova: Centrální tolerance, NF
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Defensins and autoimmunity: emerging alpha-defensin based model to study mechanisms underpinning autoimmune processes
Neuwirth, Aleš ; Filipp, Dominik (advisor) ; Černý, Jan (referee) ; Michálek, Jaroslav (referee)
The process of immune "self-nonself discrimination" is of utmost importance for the survival of all species as the biodestructive force of immune system can be directed towards the host as much as to pathogens. Thus, to shift this balance towards the latter, T cells bearing self- recognizing receptors are removed in the thymus (central tolerance) or their reactivity is harnessed through various additional mechanisms in periphery (peripheral tolerance). If the selfreactive T cells are not deleted and persist in the body, the regulation of self-tolerance can be breached, leading to the onset of autoimmunity. Presented thesis revolved around α-defensins, very effective bactericidal peptides that represent an important part of humoral innate immunity. There are two types of α-defensins: myeloid, expressed predominantly in neutrophils, and enteric, synthesized by intestinal Paneth cells. Data presented inhere are first to characterized the involvement of α-defensin- expressing cells in two types of autoimmune diseases, insulin-dependent diabetes mellitus (T1D) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The former relates to the identification of transcriptionally activated myeloid α-defensin- expressing eosinophils present in the thymus of diabetes prone rat. In...
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