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Abstract(s)
Respostas imunológicas humorais protetoras coordenadas pelas células B, quer em resposta a infeções ou à vacinação, requerem a participação de células T. Entre estas, as células T foliculares auxiliares (Tfh) emergiram como elementos-chave, fornecendo ajuda às células B e facilitando a produção de anticorpos de alta afinidade. Por outro lado, as células T foliculares reguladoras (Tfr), originárias de células T reguladoras (Treg) tímicas nos tecidos linfoides periféricos, assumem o papel de orquestradoras. Elas modulam a magnitude das recções dos centros germinativos (GC) para evitar o aparecimento de clones de células B auto-reactivas, ao mesmo tempo que a produção de anticorpos protetores é otimizada. Deste modo, manter este delicado equilíbrio entre a produção de anticorpos e a autoimunidade depende imensamente das subpopulações celulares Tfh e Tfr. Apesar da extensa investigação sobre células Tfh desde a sua descoberta, as células Tfr só ganharam destaque recentemente. Mais de uma década de investigação sobre as células Tfr tem vindo a revelar algumas disparidades na sua biologia em comparação com as células Tfh, desafiando a suposição da sua estreita semelhança. Apesar da sua importância (uma vez que a sua ausência está associada ao desencadeamento de doenças autoimunes), persistem lacunas significativas na compreensão da biologia das células Tfr, proporcionando um vasto campo para exploração e descoberta. A presente tese pretende iluminar o mundo intrincado das células Tfr, procurando refinar a sua definição e elucidar o seu processo de diferenciação. A nossa investigação sobre as células Tfr durante a resposta imunitária em murganho proporcionou uma caracterização mais completa do seu fenótipo e das moléculas que governam a sua trajetória de desenvolvimento. Apesar da ontogenia reguladora partilhada, descobrimos diferenças significativas no fenótipo e na diferenciação das células Tfr em comparação com as células T reguladoras efetoras. Simultaneamente, demonstrámos que duas moléculas expressas na membrana e amplamente utilizadas para identificar as células Tfh e Tfr, o ICOS e o PD-1, exibem padrões distintos durante a diferenciação destas populações de células em humanos. Enquanto o ICOS e o PD-1 podem ser utilizados de forma intercambiável para a identificação das células Tfh, o ICOS é expresso antes da expressão de PD-1 nas células Tfr. Esta observação levou à delimitação de três fases distintas de desenvolvimento das células Tfr nos tecidos linfoides humanos. Adicionalmente, as nossas descobertas sugerem que o OX40L e o IL-6 podem desempenhar papéis cruciais na indução do programa de diferenciação das células Tfr nas células Treg humanas. No seu conjunto, os resultados obtidos nesta tese fornecem novas perspetivas sobre a caracterização e diferenciação das células Tfr. Além disso, proporcionam oportunidades para investigações futuras na modulação da resposta dos GC e no papel de moléculas específicas, identificadas neste estudo, na função das células Tfr.
Protective humoral immune responses orchestrated by B cells, whether in response to infection or vaccination, require the involvement of T cells. Among these, T follicular helper (Tfh) cells have emerged as key players, enhancing B cell help and facilitating the production of high-affinity antibodies. Conversely, T follicular regulatory (Tfr) cells, arising from thymic T regulatory (Treg) cells within peripheral lymphoid tissues, assume the role of orchestrators. They modulate the magnitude of the germinal center (GC) reactions to prevent the emergence of autoreactive B cell clones while optimizing the generation of protective antibodies. Maintaining this delicate equilibrium between antibody production and autoimmunity relies heavily on both Tfh and Tfr subsets. Despite extensive research on Tfh cells since their discovery, Tfr cells have only recently come into focus. Over a decade of research on Tfr cells has uncovered intriguing disparities in their biology compared to Tfh cells, challenging the assumption of their close resemblance. Despite their critical importance (as their absence is associated with the onset of autoimmune conditions), significant gaps persist in our understanding of Tfr cell biology, offering a rich avenue of exploration and discovery. The present thesis endeavors to shed light on the intricate world of Tfr cells, seeking to refine their definition and elucidate their developmental pathways. Our investigation into Tfr cells during the immune response in mice has provided a more comprehensive characterization of their phenotype and the molecules governing their developmental trajectory. Despite their shared regulatory ontogeny, we have uncovered significant differences in the phenotype and differentiation of Tfr cells compared to effector Treg cells. Simultaneously, we have shown that two widely used cell-surface molecules for identifying Tfh and Tfr cells, ICOS and PD-1, exhibit distinct patterns during the differentiation of these cell populations in humans. While ICOS and PD-1 can be used interchangeably for the identification of Tfh cells, ICOS is upregulated prior to PD-1 expression in Tfr cells. This observation has led to the delineation of three distinct developmental stages within Tfr cells from human lymphoid tissues. Furthermore, our findings suggest that OX40L and IL-6 may play pivotal roles in inducing the Tfr differentiation program in human Treg cells. Altogether, the results obtained in this thesis provide fresh insights on the characterization and generation of Tfr cells. Additionally, they pave the way for further research into modulating the GC response and investigating the role of specific molecules discovered in this study in the function of Tfr cells.
Protective humoral immune responses orchestrated by B cells, whether in response to infection or vaccination, require the involvement of T cells. Among these, T follicular helper (Tfh) cells have emerged as key players, enhancing B cell help and facilitating the production of high-affinity antibodies. Conversely, T follicular regulatory (Tfr) cells, arising from thymic T regulatory (Treg) cells within peripheral lymphoid tissues, assume the role of orchestrators. They modulate the magnitude of the germinal center (GC) reactions to prevent the emergence of autoreactive B cell clones while optimizing the generation of protective antibodies. Maintaining this delicate equilibrium between antibody production and autoimmunity relies heavily on both Tfh and Tfr subsets. Despite extensive research on Tfh cells since their discovery, Tfr cells have only recently come into focus. Over a decade of research on Tfr cells has uncovered intriguing disparities in their biology compared to Tfh cells, challenging the assumption of their close resemblance. Despite their critical importance (as their absence is associated with the onset of autoimmune conditions), significant gaps persist in our understanding of Tfr cell biology, offering a rich avenue of exploration and discovery. The present thesis endeavors to shed light on the intricate world of Tfr cells, seeking to refine their definition and elucidate their developmental pathways. Our investigation into Tfr cells during the immune response in mice has provided a more comprehensive characterization of their phenotype and the molecules governing their developmental trajectory. Despite their shared regulatory ontogeny, we have uncovered significant differences in the phenotype and differentiation of Tfr cells compared to effector Treg cells. Simultaneously, we have shown that two widely used cell-surface molecules for identifying Tfh and Tfr cells, ICOS and PD-1, exhibit distinct patterns during the differentiation of these cell populations in humans. While ICOS and PD-1 can be used interchangeably for the identification of Tfh cells, ICOS is upregulated prior to PD-1 expression in Tfr cells. This observation has led to the delineation of three distinct developmental stages within Tfr cells from human lymphoid tissues. Furthermore, our findings suggest that OX40L and IL-6 may play pivotal roles in inducing the Tfr differentiation program in human Treg cells. Altogether, the results obtained in this thesis provide fresh insights on the characterization and generation of Tfr cells. Additionally, they pave the way for further research into modulating the GC response and investigating the role of specific molecules discovered in this study in the function of Tfr cells.
Description
Keywords
Centros germinais Células T foliculares auxiliares Células T foliculares reguladoras Células T reguladoras Diferenciação Germinal centers T follicular helper cells T follicular regulatory cells T regulatory cells Differentiation