Innate-like T cells specific for microbial metabolites: thymic development and interactions with the microbiota in vivo – MAIT

Mucosal Associated Invariant T cells (MAIT) are an evolutionary conserved subset recognizing vitamin B2 metabolites presented by the MHC class Ib molecule, MR1. MAIT cells have emerged as a key T cell subset because of their wide anti-microbial specificity, high inter-species conservation and abundance in human blood (1-8% of T cells), liver (20-50%) and mucosal tissues (1-10%). MAIT cells are implicated in several infectious and non-infectious pathologies, including inflammatory bowel disease, multiple sclerosis, diabetes, and obesity, and thus represent an important health issue.

We recently demonstrated that the effector functions and tissue-homing capacities of MAIT cells are acquired during thymic development1, but the molecular mechanisms involved are unclear. It is also unknown whether the MAIT transcriptional program is conserved across Mammals. In the periphery, MAIT cells play a role in host-commensals interactions, but how the microbiota activates MAIT cells is also unknown. Using my expertise in studying the development of antigen-specific T cells and building on strong preliminary data, I will:
1. Determine how MAIT cells acquire innate-like functions in the thymus. I will use single-cell RNAseq and dedicated transgenic mice to identify the molecular pathways controlling the innate-like phenotype of MAIT cells. I will characterize the transcriptional program of metabolite-specific T cells in several Mammals and define transcription factors expressed along MAIT cell thymic development.
2. Determine how MAIT cells are activated during intestinal inflammation. I will use metagenomics and modified bacteria to identify factors controlling MAIT antigen production by the microbiota.
3. Elucidate how commensal bacteria control the development of MAIT cells. I will use gnotobiotic mice and strains of bacteria modified for their ability to produce MAIT ligands to define the role of commensal bacteria in MAIT cell ontogeny.

Altogether, this project may provide new targets for modulating the development and function of a major T cell subset. Identifying factors controlling the production of MAIT antigens by the microbiota will help us prevent or promote MAIT cell activation in patients. This proposal will provide insights into an evolutionary conserved interaction between the mammalian immune system and the intestinal microbiota.