Spatial transcriptomics identifies fibroblast–T cell crosstalk as a driver of Th2 polarization in allergic rhinitis

Background Allergic rhinitis (AR) is a common chronic nasal mucosal inflammatory disorder driven by type 2 immunity, but the spatial stromal–immune cell interactions underlying its pathogenesis remain unclear. Methods We used 10x Genomics Xenium In Situ spatial transcriptomics to map the nasal mucosa of 10 AR patients and 10 non-allergic controls, combined with unsupervised cell clustering, differential gene expression (DE) analysis of COL1A1 + PDGFRA + fibroblasts, qRT-PCR validation, ligand–receptor modeling (CellPhoneDB/NicheNet), and multimodal integration of spatial, transcriptional, and clinical data. Results Nine major cell types with tissue-specific localization were identified. The AR samples showed expanded fibroblast-rich regions (34.2 ± 3.1% vs. 15.6 ± 2.4% in controls; p 0.001) and increased adjacency between CD4 + T cells and fibroblasts (62.3 ± 4.5% vs. 28.7 ± 3.8% in controls; p 0.001). The fibroblasts in AR had 187 upregulated genes (e.g., TSLP, IL33) that were spatially enriched near CD4 + T cells and validated by qRT-PCR. CD4 + T cells within 20 μm of fibroblasts in AR showed higher Th2 cytokine expression (IL4, IL5, IL13) and Th2/GATA3 signature scores ( p 0.001). Three key ligand–receptor axes (TSLP–IL7R, OX40L–OX40, and ICOSL–ICOS) drove the fibroblast–Th2 crosstalk. A “fibroblast–T cell crosstalk score” was ×4.8 higher in AR ( p 0.001) and correlated with clinical severity (serum IgE: r = 0.71; SPT wheal diameter: r = 0.65; p 0.001). Conclusions AR is defined by expanded fibroblast niches, fibroblast-derived type 2 mediators, and ligand–receptor-dependent fibroblast–Th2 crosstalk—a central pathogenic driver and potential therapeutic target.