Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis

Detalhes bibliográficos
Autor(a) principal: Sousa, Laura Isabel Guedes de
Data de Publicação: 2018
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10773/25530
Resumo: The immune system possesses unique mechanisms to cope with environmental threats. Among these mechanisms, functional selftolerant T lymphocytes represent a critical member of the adaptive immune system and their development rely on instructive signals provided by the unique microenvironments of the thymus. Here, cortical (c) and medullary (m) thymic epithelial cells (TECs) comprise two distinct lineages with well-defined roles in T cell selection and tolerance induction. While little is known concerning the mechanisms that control TEC homeostasis, recent data from the host lab positioned the tumor protein p53 as a new molecular determinant of TEC biology. The conditional deletion of p53 on the thymic epithelium compromised the integrity of the mTEC niche. These alterations negatively influenced thymic functioning, which ultimately contributed to a reduced peripheral T cell pool in mutant mice. In this thesis, we aimed at investigating the cellular and molecular basis behind the altered T cell compartment in p53cKO mice. Our extensive in vivo and in vitro characterization revealed no obvious defects on the functional and homeostatic capacity of p53cKO-derived T cells. Yet, we noticed that mature single positive thymocytes of p53cKO mice present an ineffective upregulation of the sphingosine-1- phosphate receptor 1 (S1PR1), pointing for the possible existence of an altered thymic output. Using adoptive transfer of RAG-GFP bone marrow-derived cells, we found a reduction in the number of recent thymic emigrants (RTEs) that are present in the spleen of p53cKO mice. Collectively, our results suggest that the targeted deletion of p53 on the thymic epithelium had a severe impact on the thymic export of p53cKO mice, which contributed for a smaller peripheral T cell compartment.
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spelling Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasisThymusTECsT cellsp53thymic exportS1PR1RTEsThe immune system possesses unique mechanisms to cope with environmental threats. Among these mechanisms, functional selftolerant T lymphocytes represent a critical member of the adaptive immune system and their development rely on instructive signals provided by the unique microenvironments of the thymus. Here, cortical (c) and medullary (m) thymic epithelial cells (TECs) comprise two distinct lineages with well-defined roles in T cell selection and tolerance induction. While little is known concerning the mechanisms that control TEC homeostasis, recent data from the host lab positioned the tumor protein p53 as a new molecular determinant of TEC biology. The conditional deletion of p53 on the thymic epithelium compromised the integrity of the mTEC niche. These alterations negatively influenced thymic functioning, which ultimately contributed to a reduced peripheral T cell pool in mutant mice. In this thesis, we aimed at investigating the cellular and molecular basis behind the altered T cell compartment in p53cKO mice. Our extensive in vivo and in vitro characterization revealed no obvious defects on the functional and homeostatic capacity of p53cKO-derived T cells. Yet, we noticed that mature single positive thymocytes of p53cKO mice present an ineffective upregulation of the sphingosine-1- phosphate receptor 1 (S1PR1), pointing for the possible existence of an altered thymic output. Using adoptive transfer of RAG-GFP bone marrow-derived cells, we found a reduction in the number of recent thymic emigrants (RTEs) that are present in the spleen of p53cKO mice. Collectively, our results suggest that the targeted deletion of p53 on the thymic epithelium had a severe impact on the thymic export of p53cKO mice, which contributed for a smaller peripheral T cell compartment.O sistema imunitário possui mecanismos de defesa que lhe permitem enfrentar as ameaças que existem no ambiente externo. Entre estes mecanismos, os linfócitos T funcionais e tolerantes ao próprio representam um elemento indispensável do sistema imune adaptativo e a sua diferenciação está dependente de sinais provenientes do timo. Neste, as células epiteliais do timo (TECs), que podem ser divididas em células epiteliais corticais (cTECs) ou medulares (mTEC), contribuem para a sua seleção e para a indução de tolerância. Apesar de os mecanismos que controlam a homeostasia das TEC não estarem completamente estabelecidos, estudos recentes do nosso laboratório demonstraram a importância da proteína tumoral p53 para o controlo desta homeostasia. A deleção específica do p53 no epitélio tímico compromete a integridade do nicho de mTECs. Estas alterações influenciaram negativamente a função tímica, na medida em que culminaram na redução das células T periféricas nos animais mutantes. Nesta tese pretendemos investigar os mecanismos celulares e moleculares que poderiam explicar o compartimento periférico alterado nos ratinhos p53cKO. As nossas caracterizações extensivas feitas in vitro e in vivo revelaram que não existem defeitos a nível da homeostasia e da funcionalidade das células T nos animais mutantes. No entanto, verificámos que os timócitos maduros apresentavam uma expressão defeituosa do recetor de esfingosina-1-fosfato (S1PR1), o que poderia indicar que estes animais possuíam um exporte tímico alterado. De fato, através de transferências adotivas de células da medula óssea provenientes dos animais RAG-GFP, determinamos que o número de emigrantes recentes do timo (RTEs) se encontrava diminuído. Em conclusão, os nossos resultados demonstram que a deleção específica do p53 no epitélio tímico teve um impacto no exporte tímico dos animais mutantes e que estas alterações culminaram na redução da população de células T disponível na periferia.2020-12-20T00:00:00Z2018-12-18T00:00:00Z2018-12-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/25530TID:202240843engSousa, Laura Isabel Guedes deinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T11:49:35Zoai:ria.ua.pt:10773/25530Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:58:47.095871Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
title Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
spellingShingle Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
Sousa, Laura Isabel Guedes de
Thymus
TECs
T cells
p53
thymic export
S1PR1
RTEs
title_short Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
title_full Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
title_fullStr Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
title_full_unstemmed Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
title_sort Unravelling the functional consequences of TEC-specific deletion of p53 in T cell homeostasis
author Sousa, Laura Isabel Guedes de
author_facet Sousa, Laura Isabel Guedes de
author_role author
dc.contributor.author.fl_str_mv Sousa, Laura Isabel Guedes de
dc.subject.por.fl_str_mv Thymus
TECs
T cells
p53
thymic export
S1PR1
RTEs
topic Thymus
TECs
T cells
p53
thymic export
S1PR1
RTEs
description The immune system possesses unique mechanisms to cope with environmental threats. Among these mechanisms, functional selftolerant T lymphocytes represent a critical member of the adaptive immune system and their development rely on instructive signals provided by the unique microenvironments of the thymus. Here, cortical (c) and medullary (m) thymic epithelial cells (TECs) comprise two distinct lineages with well-defined roles in T cell selection and tolerance induction. While little is known concerning the mechanisms that control TEC homeostasis, recent data from the host lab positioned the tumor protein p53 as a new molecular determinant of TEC biology. The conditional deletion of p53 on the thymic epithelium compromised the integrity of the mTEC niche. These alterations negatively influenced thymic functioning, which ultimately contributed to a reduced peripheral T cell pool in mutant mice. In this thesis, we aimed at investigating the cellular and molecular basis behind the altered T cell compartment in p53cKO mice. Our extensive in vivo and in vitro characterization revealed no obvious defects on the functional and homeostatic capacity of p53cKO-derived T cells. Yet, we noticed that mature single positive thymocytes of p53cKO mice present an ineffective upregulation of the sphingosine-1- phosphate receptor 1 (S1PR1), pointing for the possible existence of an altered thymic output. Using adoptive transfer of RAG-GFP bone marrow-derived cells, we found a reduction in the number of recent thymic emigrants (RTEs) that are present in the spleen of p53cKO mice. Collectively, our results suggest that the targeted deletion of p53 on the thymic epithelium had a severe impact on the thymic export of p53cKO mice, which contributed for a smaller peripheral T cell compartment.
publishDate 2018
dc.date.none.fl_str_mv 2018-12-18T00:00:00Z
2018-12-18
2020-12-20T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10773/25530
TID:202240843
url http://hdl.handle.net/10773/25530
identifier_str_mv TID:202240843
dc.language.iso.fl_str_mv eng
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instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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