Thymus autonomy

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Defesa de Tese

 

Pode consultar o resumo desta defesa de tese em inglês.

President of the Jury – Doutora Mariana Pinho, Professora Associada, do Instituto de Tecnologia Química e Biológica Antonio Xavier da Universidade Nova de Lisboa

Jury members:
- Doutora Cláudia Waskow, Professora Catedrática, Leibninz Institute on Aging- Fritz Lipmann Institute, Alemanha – main jury member;
- Doutora Ana Cumano, Investigadora Principal, Institute Pasteur, França – main jury member;
- Doutor Jonathan Charles Howard, Investigador Principal, Instituto Gulbenkian de Ciência (IGC) – jury member;
- Doutor Miguel Che Parreira Soares, Investigador Principal, Instituto Gulbenkian de Ciência (IGC) - jury member;
- Doutora Vera C. Martins, Investigadora Principal, Instituto Gulbenkian de Ciência (IGC) – supervisor.

Abstract:
This thesis focuses on T lymphocyte development in the steady-state and in conditions permissive to T cell acute lymphoblastic leukemia (T-ALL). Specifically, we were interested in how thymocytes differentiate in homeostasis and how healthy thymocytes can transform to originate leukemia. First, we focused on the early T lineage progenitor (ETP), the most immature thymocyte population in the thymus. We found that ETPs that have recently seeded the thymus rely on Interleukin 7 (IL-7) and IL-7 receptor (IL-7r). At this stage, IL-7/IL-7r signaling drives proliferation and survival of ETPs thereby establishing the normal population of progenitors that initiate thymopoiesis. Next, we challenged T lymphocyte development by compromising the supply of competent bone marrow-derived progenitors to the thymus. Steady-state thymopoiesis is characterized by a high cellular turnover that is guaranteed by the constant influx of new progenitors. However, if this flow is impaired the thymus can autonomously sustain T lymphocyte development for several weeks, a process termed thymus autonomy. Importantly, prolongation of thymus autonomy leads to T-ALL. To study these processes, we used a thymus transplantation model in which wild type thymi were grafted into Rag2-/-γc-/- mice. The hematopoietic progenitors of the host that seed the thymus grafts cannot drive thymocyte turnover and are, thereby, permissive to thymus autonomy. We found that a population of donor CD4-CD8- double negative 3 early (DN3e) thymocytes transiently acquires self-renewal capacity while also differentiating in vivo to secure autonomous thymopoiesis. Moreover, autonomous DN3e had increased proliferation associated to substantial transcriptional changes, including Notch1 target genes. We further detailed thymus autonomy using single cell RNA sequencing and found that it retained the hallmarks of steady-state thymopoiesis, following the canonical differentiation steps from the DN3 stage. However, thymus autonomy was also associated with defects in the β-selection checkpoint leading to the emergence of CD4+CD8+ double positive thymocytes lacking productive TCRβ rearrangements and with an atypical Notch1 target gene signature, suggestive of an early step in the transformation process towards T-ALL. Altogether, we propose that thymus autonomy is an intrinsic feature of the thymus that is kept inhibited in the steady-state. As prolonged thymus autonomy leads to T-ALL, keeping it inhibited or tightly restricted in time is crucial. This is particularly relevant when designing new experimental therapies that involve the manipulation of T lymphocyte development.

 


ORADOR

Rafael Paiva
Instituto Gulbenkian de Ciência

 

ORGANIZADOR
IBB2016 e Vera Martins

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