ThymEForT · Dissecting the role of thymic epithelial cells in T lymphocytes maturation during human foetal development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2024-01-05
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Dissecting the role of thymic epithelial cells in T lymphocytes maturation during human foetal development
The thymus plays an essential role in the establishment of adaptive immunity and central tolerance as it provides a nurturing environment for the differentiation of T cells, a process orchestrated by their interaction with multiple cell types. Despite advances in the knowledge of human thymus biology, how it functionally develops remains elusive. This project aimed at dissecting molecular mechanisms responsible for functional maturation of T cells by recapitulating human thymic development within a novel in vitro 3D system. Epithelial and T cell compartments were isolated and characterised at relevant developmental stages to underpin when thymic stroma acquires competence to sustain the production of functional T cells. We identified an epithelial stem cell population that sustain thymic function. Thymic epithelial stem cells self-renew in vitro and differentiate into specialised epithelial cell types that, when cocultured with T-cell progenitors, give rise to mature thymocytes within a unique 3D thymic natural matrix. After characterising the thymic epithelial compartment at single-cell level, we uncovered a new medullary progenitor population expressing specific transcription factors. Thymic epithelial stem/progenitor cells were genetically modified in vitro to knock-out these novel genes to explore whether they impact on T cell maturation. Finally, this project has revealed that human thymic epithelial stem cells can be co-cultured with thymocytes progenitors within a novel, whole human 3D system. This allows to tackle fundamental immunological questions regarding human thymus development including maturation of T cells and regulation of central tolerance. In addition, this will lay the foundation to develop new treatments for thymic diseases and for congenital immune deficiencies based upon correction of the underlying molecular defects.
Data: CORDIS, © European Union
Project objective
The thymus plays an essential role in the establishment of adaptive immunity and central tolerance as it provides a nurturing environment for the differentiation of T cells, a process orchestrated by their interaction with multiple cell types. Despite advances in the knowledge of human thymus, how it functionally develops during foetal life remains elusive. This project aims at dissecting molecular mechanisms responsible for functional maturation of T cells by recapitulating human foetal development within a novel in vitro 3D system. Stromal and T cell compartments will be isolated and characterised at relevant developmental stages before and after mature T cells appear to underpin when thymic stroma acquires competence to sustain T cell development. Stromal populations from relevant developmental stages will be expanded in vitro to be cocultured with T progenitors within a unique 3D thymic natural matrix developed by the host lab. Repopulated 3D scaffold is sliced according to clinical grade protocols and cultured, allowing to set up multiple coculture conditions with the same stroma and compare the output on T cell maturation. In parallel, foetal thymic epithelial cells will be genetically modified to determine the role of specific transcription factors important for T cells onset during development. Recently developed microfluidic devices will provide an additional layer of information regarding molecular mechanisms regulating the crosstalk between stromal and immunological compartments. I anticipate to recapitulate human T cell development within a novel, whole human 3D in vitro culture system, to tackle fundamental immunological questions regarding human thymus development including maturation of tolerogenic T cells and regulation of central tolerance. Last, new key molecular and cellular players for T-cell specification will be uncovered opening new avenues for both congenital immune deficiencies based upon correction of the underlying molecular defect.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
- View on CORDIS
- DOI: 10.3030/896014
- https://www.crick.ac.uk/research/find-a-researcher/roberta-ragazzini
Data: CORDIS, © European Union