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Generation of tissue-resident memory T cells
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O sistema imune pode ser dividido em dois ramos principais, imunidade inata e imunidade adaptativa. Enquanto a imunidade inata reconhece padrões conservados em microrganismos ao longo da evolução, a imunidade adaptativa atua de forma especializada, através de linfócitos B e T. Estas células são capazes de reconhecer moléculas de patogénios com maior especificidade e combate-los mais eficazmente, eliminando-os na maior parte dos casos. Além desta função, uma característica fundamental da imunidade adaptativa e a geração de memoria imunológica. Desta forma, se um organismo for reinfectado com um patogénio, a resposta imune contra este será muito mais rápida e poderá decorrer sem doença. Inicialmente, as células T de memoria eram divididas em dois grupos de acordo com os órgãos pelos quais circulavam: células T de memoria efetora, que circulam em órgãos não linfoides, e células T de memoria central, assim conhecidas por apresentarem uma maior longevidade e terem um maior tropismo para órgãos linfoides. Mais recentemente novos grupos de células de memoria foram descritos, nomeadamente as células T de memoria residentes em tecidos (Trm). Como o nome indica, estas células estão destinadas a permanecer dentro dos tecidos onde foram geradas, expressando marcadores como CD69, que previne a sua saída, e CD103 ou CD49a, que lhes permite a integração no tecido e o seu patrulhamento. Para que a memoria imunológica seja gerada, uma resposta imune efetora tem de ser estabelecida previamente. A resposta de células T pode ser dividida classicamente em três grupos, de acordo com o tipo de patogénio encontrado. No caso de infeção por vírus ou bactérias intracelulares, há um contexto inflamatório que promove a diferenciação do linfócito T CD4 em linfócito T auxiliar do tipo 1 (Th1). Este processo e desencadeado por um programa transcricional mediado pelo fator de transcrição T-box expresso em células T (Tbet), que leva a produção de interferão gama (IFN-g). Por sua vez, o IFN-g ativa macrófagos e recruta linfócitos T CD8 citotóxicos, de forma a eliminar células infetadas. No contexto duma infeção helmíntica, ou em caso de alergia, uma resposta mediada por IL-4 induz o linfócito T a iniciar um programa de diferenciação em célula T auxiliar do tipo 2 (Th2). Este programa e orquestrado pelo fator de transcrição GATA-3, que promove a produção de interleucina (IL)- 4, IL-5 e IL-13, e também o recrutamento de eosinófilos, basófilos e mastócitos, que desencadeiam mecanismos de reparação tecidual. Se o patogénio tiver uma natureza extracelular, seja bactéria ou fungo, ira desencadear uma resposta mediada por IL-6 e TGF-b, que levara um linfócito T a diferenciar-se numa célula T auxiliar produtora de IL-17 (Th17). Este fenómeno traduz-se através do recetor retinoide órfão gama t (RORgt), que despoleta a expressão de IL-17 e IL-22 na célula Th17, promovendo o recrutamento de neutrófilos para o local de infeção e induzindo a fagocitose do patogénio.
The immune system consists of two related branches, the innate immunity and the adaptive immunity. The latest has one key feature that is particularly important, the generation of memory. Immunological memory is critical for immune protection, particularly at epithelial sites, which are under constant risk of pathogen invasions. The first classifications of T cell memory considered two groups of cells, the central memory T cells (Tcm), recirculating through lymphoid organs, and effector memory T cells (Tem), recirculating through non-lymphoid tissues, the first being longer-lived, and the latter having a shorter living period, but a higher capacity of clonal expansion and potent response. A more recently described group of CD8 memory T cells develops at the location of infection: tissue-resident memory T cells (Trm), which are prevented from egressing the tissues they home to, and act as a first line of defense against invading pathogens. To control T cell responses and prevent tissue damage, regulatory T cells (Treg) are recruited to the site of infection, dampening the immune response, and promoting tissue regeneration. CD8 T-cell responses are associated with type-1 infections, and type-1 Tregs are important for CD8+ Trm cell development, however, if CD8+ Trm cells develop under other infection types and require immune type-specific Treg cells is unknown. We used three distinct lung infection models. Influenza infection confirmed that in the lung type-1 Tregs are required for normal Trm cell generation. Nippostrongylus brasiliensis showed that type-2 helminth infection does not establish CD8+ Trm cells. To study generation of Trm cells in the context of extracellular (type-3) infection by Aspergillus fumigatus, we generated a mouse model lacking specifically type-3 Tregs, without any other T cell subset affected. This model allowed us to conclude that extracellular infections do yield CD8+ Trm cells, which rely on the recruitment of a response type-matching Treg population contributing with bioactive transforming growth factor-β (TGF-b). Surprisingly, specific deletion of type-1 Treg cells also decreased Trm cell formation under Aspergillus fumigatus infection. These newly generated Trm cells maintain their commitment to their original effector phenotype, whether it be producing IFN-g or IL-17. Nevertheless, type-1 Treg cells remain the most important population for Trm cell development. These results highlight Treg cells as a new and important player in the generation of immunological memory, with potential implications in a change of paradigm on the development of vaccines inducing CD8+ Trm cells.
The immune system consists of two related branches, the innate immunity and the adaptive immunity. The latest has one key feature that is particularly important, the generation of memory. Immunological memory is critical for immune protection, particularly at epithelial sites, which are under constant risk of pathogen invasions. The first classifications of T cell memory considered two groups of cells, the central memory T cells (Tcm), recirculating through lymphoid organs, and effector memory T cells (Tem), recirculating through non-lymphoid tissues, the first being longer-lived, and the latter having a shorter living period, but a higher capacity of clonal expansion and potent response. A more recently described group of CD8 memory T cells develops at the location of infection: tissue-resident memory T cells (Trm), which are prevented from egressing the tissues they home to, and act as a first line of defense against invading pathogens. To control T cell responses and prevent tissue damage, regulatory T cells (Treg) are recruited to the site of infection, dampening the immune response, and promoting tissue regeneration. CD8 T-cell responses are associated with type-1 infections, and type-1 Tregs are important for CD8+ Trm cell development, however, if CD8+ Trm cells develop under other infection types and require immune type-specific Treg cells is unknown. We used three distinct lung infection models. Influenza infection confirmed that in the lung type-1 Tregs are required for normal Trm cell generation. Nippostrongylus brasiliensis showed that type-2 helminth infection does not establish CD8+ Trm cells. To study generation of Trm cells in the context of extracellular (type-3) infection by Aspergillus fumigatus, we generated a mouse model lacking specifically type-3 Tregs, without any other T cell subset affected. This model allowed us to conclude that extracellular infections do yield CD8+ Trm cells, which rely on the recruitment of a response type-matching Treg population contributing with bioactive transforming growth factor-β (TGF-b). Surprisingly, specific deletion of type-1 Treg cells also decreased Trm cell formation under Aspergillus fumigatus infection. These newly generated Trm cells maintain their commitment to their original effector phenotype, whether it be producing IFN-g or IL-17. Nevertheless, type-1 Treg cells remain the most important population for Trm cell development. These results highlight Treg cells as a new and important player in the generation of immunological memory, with potential implications in a change of paradigm on the development of vaccines inducing CD8+ Trm cells.
Descrição
Tese de doutoramento em Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2024
Palavras-chave
Immune response Trm Treg Infection Transcription factor Resposta imune Trm Treg Infeção Fator de transcrição