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

• 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
• topic: Thymus; TECs; T cells; p53; thymic export; S1PR1; RTEs

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.