Oral Presentation CD1-MR1 Workshop 2025

MAIT cell differentiation and tissue colonization at steady-state (#28)

Rafael A Paiva 1 , Hugues Briere 1 , Anne-Laure Le Gac 1 , Aurelie Darbois 1 , Perrin Laetitia 1 , Belmellat Anya 1 , Salou Marion 1 , Olivier Lantz 1
  1. Institut Curie, PSL University, Inserm U932, , Paris, France

MAIT cells are selected by CD4+CD8+ thymocytes presenting microbial metabolites on MR1 and, thereby, acquire PLZF and a memory-effector phenotype in the thymus. In parallel, interactions with MR1-presenting epithelial cells can select MR1:5-OP-RU-reactive T cells that remain naïve. In the periphery, the frequency of MAIT cells with different maturity and effector phenotypes vary according to the organ of residence. Here, we defined the MAIT developmental stages as: MAIT0 (CD24hi), MAIT immature1 (MAITi1, CD24alo/-PLZF-), MAITi2 (PLZF+T-bet-RORgt-), MAIT1 (PLZF+T-bet+) and MAIT17 (PLZF+RORgt+) and analyzed the impact of cell-specific MR1 expression in MAIT cell development using several approaches, including bone-marrow chimeras, thymus transplants and various cre-mouse strains. While MR1 expression by CD4+CD8+ thymocytes was necessary to induce MAIT cell maturation and PLZF expression, Mr1 deletion in thymic epithelial cells hampered MAIT cell selection leading to reduced numbers of mature MAIT cells. Surprisingly, Cd1d deletion in the thymic epithelium did not affect iNKT development. Additionally, we determined that MAIT cell egress from the thymus relies on S1PR receptors at different developmental stages, as not only MAIT1 and MAIT17 but also MAITi1 and MAITi2 cells accumulated in the thymus after treatment with S1PR-antagonist FTY720. Adoptive transfer of these subsets demonstrated tissue tropism of MAITi1 cells to lymphoid tissues, while the mature subsets colonized mucosal tissues: MAIT1 cells the liver, MAIT17 cells the lung and skin while the gut was preferentially seeded by immature MAITi2 cells. This latest subset colonized the gut in a CCR9-dependent manner and underwent further extra-thymic differentiation into MAIT1/17 (T-bet+RORgt+) cells. Lastly, we show that thymic output throughout adulthood contributes to the maintenance of tissue MAIT (and iNKT) cell pool, especially the type 17 subsets. Altogether, we propose a two-step selection process for thymic MAIT cells which acquire subset-specific tissue-tropism in the thymus and differentially colonize peripheral organs.