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Molecular control of self-renewal and lineage specification in thymic epithelial cell progenitors in vivo.

Periodic Reporting for period 3 - TEC_Pro (Molecular control of self-renewal and lineage specification in thymic epithelial cell progenitors in vivo.)

Reporting period: 2018-07-01 to 2019-12-31

The development of vaccines for the treatment of infectious diseases, cancer and autoimmunity depends on our knowledge of T-cell differentiation. This project is focused on studying the thymus, the organ responsible for the generation of T cells that are responsive against pathogen-derived antigens, and yet tolerant to self. Within the thymus, thymic epithelial cells (TECs) provide key inductive microenvironments for the development and selection of T cells that arise from hematopoietic progenitors. As a result, defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand immunity and tolerance induction. TECs are divided into two functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors (TEPs). Yet, the genetic and epigenetic details that control cTEC/mTEC lineage specifications from TEPs are unsettled.

My objectives are to identify TEC progenitors and their niches within the thymus, define new molecular components involved in their self-renewal and lineage potential, and elucidate the genetic programs that regulate cTEC/mTEC fate decision. We take a global approach to examine TEC differentiation, which integrates the study of molecular processes taking place at cellular level and the analysis of in vivo mouse models. Using advanced research tools that combine reporter mice, clonogenic assays, organotypic cultures, high-throughput screen and genome-wide transcriptomic profiling, we are dissecting the principles that underlie the self-renewal and lineage differentiation of TEC progenitors in vivo.
During the first half of the project, we have progressed at different levels on the three original goals of the project. We have identified a new subset of bipotent TEP (refereed as ClonoTEC) that nestle in the thymic cortex and whose abundance is dynamically controlled by continual interactions with thymocytes across lifespan (published in the European Journal of Immunology in 2017). These findings potentially explain how changes in TEP bioavailability impact on the maintenance of TEC niches, and ultimately on thymic output. Moreover, we have identified a novel immunoregulatory role for p53 in TECs to orchestrate their role in T-cell development and tolerance induction (published in Blood 2017 and in Trends in Immunology 2017). Our study received highlights from Blood (a companion commentary article and selection for the snapshot of “This Week in Blood”) and Science (selection for the “Editor’s Choice” section).
Our research is providing fundamental knowledge that can be considered and/or incorporated in future therapeutics to regenerate thymus function and immunity in aged individuals, patients undergoing bone marrow transplantation or under anti-cancer regimens. As such, the results obtained in this project has the potential to contribute with knowledge that can help tackling one of the great challenges of modern immunology – modulate thymic function through the induction of TEPs - and therefore, represents a major advance in Health Sciences.