Description du projet
Un modèle 3D in vitro du développement du thymus
La différenciation des lymphocytes T dans le thymus est capitale pour l’immunité adaptative et la tolérance centrale. Toutefois, le mécanisme de développement du thymus au cours de la vie fœtale reste difficile à saisir. Pour disséquer les mécanismes responsables de la maturation fonctionnelle des lymphocytes T dans le thymus, les scientifiques du projet ThymEForT, financé par l’UE, développeront un nouveau système 3D in vitro qui récapitule le thymus à différents stades de développement. À l’aide d’un échafaudage 3D ensemencé de populations stromales de stades de développement pertinents et de progéniteurs de lymphocytes T, ils évalueront leur maturation. Des travaux supplémentaires sur le rôle de facteurs de transcription spécifiques dévoileront les principaux acteurs moléculaires de la spécification des lymphocytes T et aideront à répondre aux questions immunologiques fondamentales.
Objectif
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.
Mots‑clés
Programme(s)
Appel à propositions
(s’ouvre dans une nouvelle fenêtre) H2020-MSCA-IF-2019
Voir d’autres projets de cet appelRégime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
WC1E 6BT London
Royaume-Uni