Projektbeschreibung
Die Rolle von mukosalen T-Zellen bei der Geweberegeneration
Mukosa-assoziierte invariante T-Zellen (MAIT-Zellen) sind eine spezielle T-Zellgruppe, die in der Lage ist, bestimmte mikrobielle Liganden im Schleimhautgewebe zu erkennen. Besonders interessant ist dabei, dass sich diese Zellen während der Entwicklung durch bislang unbekannte Mechanismen im Thymus ausdifferenzieren. Das Wissenschaftlerteam des EU-finanzierten Projekts MAIT wird untersuchen, wie das Gewebe und Umgebungsreize diese thymische Differenzierung beeinflussen und die MAIT-Funktion bestimmen. Der Schwerpunkt der Arbeit liegt dabei auf der Effektor- und Schutzfunktion der MAIT-Zellen bei der Wundheilung der Haut und Grippeinfektionen. Die Ergebnisse werden nicht nur grundlegendes Wissen zu dieser T-Zell-Population bereitstellen, sondern den Grundstein legen, um die Geweberegeneration durch die Verwendung von MAIT-Zellen zu verbessern.
Ziel
Mucosal associated invariant T cells (MAITs) represent an abundant subset in humans with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important, non-redundant functions. Despite changes in MAIT frequency and phenotype in several infectious and non-infectious diseases, their functions are still unclear. By contrast with mainstream CD4+ or CD8+ T cells, MAITs differentiate into effector cells during thymic development. How the differentiation program imparted in the thymus is modified by tissue and environmental cues to determine MAIT functions in tissues is not known. Our preliminary data support a new function for MAITs in boosting tissue repair in skin wound healing and flu infection. Thus, MAITs would either repair tissues or inflict tissue damage when fighting microbes according to the stage of the disease. To understand how and when the different MAIT functions are turned on and off in vivo we will study: 1) How is the thymic MAIT differentiation program modulated by tissue and environmental cues to determine the location and effector functions of MAITs in skin and lung at steady state? To this end we will develop new genetic methods to modify MAIT development or functions. 2) What are the effector functions of MAITs leading to protection during skin wound healing and flu infection? We will determine the cell types MAITs affect and identify the mediators secreted by MAIT cells. 3) What triggers MAIT protective effect? We will identify the drivers of MAIT activation and assess the requirement for cognate or non-cognate (cytokines) interactions. Wound healing of human skin explants will test the therapeutic potential of modulating MAIT activation. Our results will provide unique insight on the functions of MAIT cells with important implications for therapy of diseases in which MAIT triggering (or inhibition) could be beneficial (or deleterious) such as wounds or infections that damage tissues and thus require repair.
Wissenschaftliches Gebiet
Not validated
Not validated
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
75231 Paris
Frankreich