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ERC

TEC_Pro Report Summary

Project ID: 637843
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - TEC_Pro (Molecular control of self-renewal and lineage specification in thymic epithelial cell progenitors in vivo.)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

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 TECdifferentiation 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 TECprogenitors (TEPs). Yet, the genetic and epigenetic details that control cTEC/mTEClineage specifications from TEPs are unsettled.

My objectives are to identify TECprogenitors and their niches within the thymus, define new molecular components involved in their self-renewal and lineage potential, and elucidate the epigenetic codes that regulate the genetic programs during cTEC/mTECfate decisions. We take a global approach to examine TECdifferentiation, 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 RNAi screen and genome-wide epigenetic and transcriptomic profiling, we are dissecting the principles that underlie the self-renewal and lineage differentiation of TECprogenitors in vivo.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the first year and half of the aforementioned project, we have progressed at different levels on the three main goals initially listed in the project.
We propose to identify bipotent TEC progenitors and their niches within the fetal and adult thymus. The results obtained so far provide evidence that the cortical epithelium contains a reservoir of epithelial progenitors whose abundance is dynamically controlled by continual interactions with developing thymocytes across lifespan. These results are part of a manuscript that had a favourable review in the European Journal of Immunology and that we expect to have it published in 2017.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our research is enabling us to gain fundamental knowledge that can be applied to find ways to regenerate and repair thymus function and immunity in aged individuals, patients undergoing bone marrow transplantation or under anti-cancer regimens The results obtained in this project has the potential to contribute to 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.
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