To analyze the mechanisms of MAIT1 versus MAIT17 commitment during development, we analyzed the TCR repertoire of developing MAIT cells. The results dismissed the hypothesis that TCR avidity for the selecting ligand would be responsible for MAIT1/17 commitment as the same TCRs were found in both MAIT1 and MAIT17 subsets (PNAS, 2024) In addition, single-cell ATAC seq and scRNA seq datasets of MAIT thymocytes were generated, leading to the identification of candidate genes potentially involved in MAIT1/MAIT17 differentiation (CD1-MR1 meeting, 2024).
We completed a comprehensive study on MAIT cell development and tissue residency (Immunity, 2026, in press). We show that thymic epithelial cells select and contribute to the mature pool of MAIT but not iNKT cells, and that MAIT cells egress the thymus at several developmental stages with tropism for specific organs. We further show that increased peripheral MAIT ligands during inflammatory bowel disease (IBD) drive preferential thymic development of MAIT17 cells. We show that the MAIT17 cells specifically induced by dysbiosis during IBD in the thymus populate the intestinal mucosae thereby constituting a feedback loop to re-establish epithelial barreer integrity.
Analysis of MAIT cell relationships with the microbial environment has been completed and published (Science Immunology, 2024). We demonstrate that MAIT cells sense riboflavin derived metabolites produced by aerotolerant bacteria residing in the colon mucosa, and that colitis induces an expansion of riboflavin producing bacteria leading to increased ligand production. These ligands cross the epithelial barrier and activate MAIT cells, inducing tissue repair genes and barrier promoting mediators. Mice lacking MAIT cells are more susceptible to colitis and colitis-driven colorectal cancer.
We have analyzed the mechanisms underlying the tissue repair capacity of MAIT cells (Immunity, 2022). We show that:
1. MAIT cell repair function does not rely on cognate interaction with MR1 in the skin;
2. MAIT cells are not long-term residents in the skin;
3. repair functions are expressed at steady state;
4. MAIT cells rely on CXCR6 and CCL16 to populate the skin;
5. MAIT cells promote epithelial proliferation and angiogenesis during wound healing;
6. amphiregulin secreted by MAIT cells is necessary to accelerate skin wound healing;
7. MR1 expression on non hematopoietic cells is not necessary for MAIT mediated repair.
In parallel, we performed a comparative cross species study revealed a conserved sequence of transcriptional events underlying MAIT cell maturation across six mammalian species, with early ZBTB16 expression and co expression of TBX21 and RORC in non rodent species (Journal of Experimental Medicine, 2024). Rodents display distinct segregation of Tbet⁺ and RORγt⁺ MAIT subsets in the thymus. Integration of scRNA seq datasets highlighted a deeply conserved MAIT transcriptional program spanning 110 million years of evolution.
Finally, our results suggest that MAIT cells promote survival of influenza infected animals but are not involved in direct antiviral immunity (CD1-MR1 meeting, 2024).
