Introduction: Mucosal-associated invariant T (MAIT) cells are the most abundant unconventional T cells in the lung and can respond to bacterial, fungal, and viral challenges. We and others have recently described a potential role in promoting tissue repair. However, it is unknown what role MAIT cells play during sterile lung tissue damage.
Methods: Both wild-type (WT) and MAIT-deficient Mr1-/- mice were challenged with bleomycin to assess MAIT cells’ role in sterile lung tissue damage, which was characterized using histology and RT-qPCR. Flow cytometry, bulk and single-cell RNA sequencing (scRNA-seq), and cell adoptive transfer were used to examine MAIT cells’ coordination with other immune cells during lung tissue damage responses, which were further assessed by analyzing published human scRNA-seq data from idiopathic pulmonary fibrosis (IPF) patient lungs.
Results: In vivo bleomycin challenge caused significant recruitment and activation of pulmonary MAIT cells and induced their tissue repair program. Mr1-/- mice exhibited more severe weight loss and tissue damage post-bleomycin challenge compared with their WT counterparts. scRNA-seq cell-cell communication analysis reveals that the absence of MAIT cells disrupted lung cell interactions. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1), limiting tissue damage in a DNGR-1-dependent manner rather than altering cDC1 functionality. The heightened tissue damage and weight loss of Mr1-/- mice were rescued by adoptive transfer of Flt3L-generated bone marrow-derived dendritic cells (FLT3L-BMDC) but DNGR-1 blockade negated this effect. Human scRNA-seq data revealed activated lung MAIT cells and increased cDC populations in IPF patients. Further analysis of cell-cell interactions revealed an active role of MAIT cells in mediating cellular communications in the lungs of IPF patients compared with healthy controls.
Conclusion: Our data suggest that MAIT cells enhance defence against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways, suggesting their potential role in modulating fibrosis in human IPF.