Descripción del proyecto
Desarrollo de linfocitos T invariantes asociados a las mucosas
Los linfocitos T invariantes asociados a las mucosas (MAIT, por sus siglas en inglés) son un subconjunto único de linfocitos T que tienen una gran importancia en la defensa inmunitaria, sobre todo en zonas con mucosas como, por ejemplo, el intestino, los pulmones y otros tejidos de barrera. Expresan un receptor de linfocitos T semi-invariante que reconoce metabolitos microbianos. El proyecto MAIT-TraDe, financiado por las acciones Marie Skłodowska-Curie, tiene por objeto comprender cómo se desarrollan y migran los linfocitos MAIT desde el timo hasta los tejidos mucosos. Sus investigadores estudiarán el papel de los metabolitos microbianos en la adaptación de los linfocitos MAIT y su mantenimiento en los tejidos. En conjunto, los descubrimientos del proyecto revelarán los mecanismos básicos que rigen la biología y la función homeostática de los linfocitos MAIT.
Objetivo
Mucosal-associated invariant T (MAIT) cells colonize mucosal tissues where they become tissue-resident and have important protective and homeostatic functions. MAIT cells are selected in the thymus by microbial metabolites presented by MHC-related protein 1 (MR1) on thymocytes thereby acquiring an effector phenotype (type 1 or 17). This project aims at elucidating mechanisms that regulate the last stages of thymic MAIT cell development, including their egress, and identify cues necessary for tissue colonization. Specifically, we will couple transcriptomics and thymus transplantation models to analyze canonical thymic MAIT cell development, thereby identifying new regulators of the MAIT1/17 fates, as well as to identify MAIT cells that recently exited the thymus and seeded mucosal organs, thereby identifying new regulators of tissue adaptation. These targets will be functionally tested in models combining CRISPR/Cas9 encoded by lentivirus with bone-marrow chimeras or adoptive transfers. Additionally, we will determine the identity and dynamics of MAIT cells exiting the thymus to colonize tissues by combining different experimental approaches including in vivo EdU/biotin labeling, thymectomy and blockage of thymus egress. Lastly, we will address whether MR1–microbial metabolites are required for the maintenance of MAIT cells in tissues at steady-state using mono-colonization/decolonization of germ-free mice and by conditionally ablating Mr1. Overall, this work will uncover fundamental mechanisms underlying MAIT cell development and tissue colonization. Albeit outside the scope of this work, it is possible that the mechanisms uncovered here may have implications in other innate-like T cells or for the establishment of mainstream tissue-resident T cells.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
75231 Paris
Francia