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

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. 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. 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). 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.