Abstract Rationale Mucosal-associated invariant T (MAIT) cells play a role in protecting against lung injury1, but the spatial interactions and mechanisms underlying their action remain poorly understood. This study aims to explore how MAIT cells influence lung injury by identifying their spatial interactions within the lung tissue and the mechanisms they use to modulate local immune responses. Methods Using single-cell resolution spatial transcriptomics (MERSCOPE), we profiled over 1.8 million cells from 14 lung tissue sections collected across seven time points from bleomycin-treated wild-type and MAIT cell-deficient Mr1−/− mice. This allowed us to identify distinct cellular niches and the interactions between various immune cells during lung injury. Results We identified seven conserved cellular niches, with alveolar niches reducing, immune and fibrotic niches expanding after injury. Fibrotic niches featured fibroblast-macrophage co-localisation, with interstitial macrophages (IM) expressing both pro-fibrotic and reparative signatures. B cell follicles emerged in immune niches, showing CXCL13 expression in B cells, goblet cells and CD4+ T cells. cDC1, regulatory T cells, and γδ T cells were spatially enriched near MAIT cells. In Mr1−/− mice, injury induces increased expression of pro-fibrotic and pro-inflammatory genes across multiple cell types compared to wild-type mice. cDC1s close to MAIT cells upregulated activation markers such as Xcr1, Flt3, and Ccr2, while nearby T cells expressed higher levels of supression marker Ctla4. Spatial analysis (using Spacia) revealed that MAIT cell-derived Ctla4, Pdcd1, and Tgfb1 were associated with reduced expression of pro-inflammatory genes (Il6, Ccl2, Ereg) in surrounding immune cells, particularly cDC1 and naïve CD4+ T cells. Re-analysis of human pulmonary fibrosis spatial transcriptomic data confirmed the presence of CXCL13+ B cell follicles and an increased MAIT cell gene signature in fibrotic lungs, mirroring murine findings. Conclusion This study provides the first spatially resolved map of MAIT cell interactions in lung injury, highlighting their role in modulating local immune responses. The data suggest that MAIT cells contribute to controlling inflammation and fibrosis in the lung, with potential implications for therapeutic strategies in lung injury and pulmonary fibrosis. Reference 1. Zhang, X. et al. MAIT cells protect against sterile lung injury. Cell Reports. 44, 115275 (2025). This abstract is funded by: Wellcome Trust
Zhang et al. (Fri,) studied this question.