Background: MAIT cells express transcriptional signatures associated with tissue repair both in vitro and in vivo. Previous transcriptomic studies from our lab and others indicate a dependency on TCR-mediated signals for this effect. However, the direct mediators of MAIT cell-directed tissue repair in human tissues have not been defined. The aim of our study is to identify such factors and their in vivo relevance, especially in the liver, where human MAIT cells are particularly abundant.
Methods: Peripheral blood PBMCs and isolated MAIT cells from healthy donors were stimulated via their TCR, with cytokines, or with both stimuli for 72h. The concentration of growth factors in these culture supernatants was quantified using LEGENDplex. MAIT cell supernatants with or without blocking antibodies were used in wound-healing assays with Caco-2 and HHL12 cell monolayers to functionally validate the importance of specific factors in tissue repair. Published single-cell RNA-seq datasets were explored to address in vivo expression of identified factors.
Results: PBMCs and MAIT cells activated with TCR+cytokines produced GM-CSF, VEGF, PDGF-AA and M-CSF. Interestingly, we found that VEGF production by MAIT cells was significantly higher than conventional T cells. In an in vitro wound healing assay, supernatants of activated sorted MAIT cells accelerated wound closure, an effect that could be blocked by anti-VEGFR2. Interrogation of a scRNA-seq data from a human experimental model showed MAIT cell expression of VEGF in vivo was associated with regenerating liver tissue.
Conclusions: Our data suggest that TCR dependent and independent signals synergistically contribute to the production of growth factors in MAIT cells. Our data indicate a key role for VEGF-VEGFR2 signalling in MAIT cell-mediated tissue repair and potentially in the unparalleled ability of the liver to undergo regeneration following injury.