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. In this project, we will assess how the differentiation program generated in the thymus is modified by tissue and environmental cues to determine the positioning and effector functions of MAITs in the skin at steady state. This will provide the grounds to determine the way MAITs are protective in skin wound healing using new genetic tools, gnotobiotic experiments and new chemical compounds. The three aims of this project are: 1. MAIT development in the thymus versus tissue and environmental cues determining the positioning and properties of MAIT cells in the skin at steady state: What are the transcription factors or genes involved in MAIT1 and MAIT17 commitment and trafficking/retention in the skin? What are the integrins/chemokines or other mediators involved in MAIT positioning in the skin? What are the roles of MR1 and MAIT ligand and bacteria in seeding and maintaining MAIT subsets in the skin? This will provide the grounds to genetically manipulate the functions of MAITs in the following aims to decipher the mechanisms involved in the protective effect of MAITs during skin wound healing. 2. To study the effector functions of MAITs leading to protection during skin wound healing: Is the protective effect mediated directly by MAITs or through the recruitment of other cell types? What are the mediators secreted or expressed by MAITs? Which MAIT subsets are involved? When and where the tissue repair functional effector modules are expressed by MAITs during the different phases of skin wound healing? 3. To study the way MAIT protective functions are triggered during skin wound healing: Are MAITs activated through cognate (TCR/Antigen) or non-cognate (lymphokine) cues? Are MAITs recruited or do they proliferate in situ during tissue repair? Is activating or inhibiting MAITs beneficial or deleterious during skin wound healing? We will also test the therapeutic potential of activating MAITs in humans.