Role of MR1-driven signals and amphiregulin on the recruitment and repair function of skin MAIT cells

Abstract

Abstract Epithelial repair is crucial to reestablish adequate barrier integrity and function after tissue injury. In both mice and humans, MAIT (Mucosal associated invariant T) cells involvement in tissue repair is substantiated by their upregulation of tissue repair mediators following TCR-mediated activation. Additionally, in the absence of ɣδT cells, MAIT cells were shown to promote wound healing. By using both our congenic B6-MAIT CASTstrain (10× more MAIT cells than B6 mice) and a skin excision mouse model preventing epithelial contraction (mimicking the human repair process), we sought to uncover the underlying mechanisms of MAIT cell tissue repair function. Firstly, our scRNAseq analysis revealed that steady-state skin MAIT cells readily express a repair program. Additionally, we show that MAIT cells have a pro-repair function as their presence promotes keratinocyte proliferation, thereby accelerating healing. Using parabiosis, skin graft and the Kaede models, we found that, contrary to the resident ɣδT cells, MAIT cells are rapidly recruited into the inflamed skin. Parabiosis of MR1 +and MR1 −mice and MR1 −skin grafted onto MR1 +mice, showed that this recruitment was MR1-independent (MR1: antigen presenting molecule of MAIT cells). Instead, this recruitment relied on the chemokine receptor CXCR6 and its ligand CXCL16. Lastly, using conditional knock-out mice we demonstrated that the secretion by MAIT cells of the amphiregulin growth factor promotes skin wound healing. Overall, our study provides mechanistic insights into MAIT cell biology in the context of injury. Comprehension of these processes provides clues into the biology of related innate subsets and highlights potential new therapeutic avenues for wound healing. Institut National de la Santé et de la Recherche Médicale (OL) Institut Curie (OL) Agence Nationale de la Recherche Grant MAIT ANR-16-CE15-0020-01 (OL) Agence Nationale de la Recherche Grant MAITrepair ANR-20-CE15-0028-01 (OL) Agence Nationale de la Recherche ANR-10-IDEX-0001-02 PSL (OL) European Research Council (ERC-2019-AdG-885435) (OL) Fondation pour la Recherche Médicale, grant number FDT202106013036 (AdH)