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

<h4>Background</h4>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.<h4>Methods</h4>We used 10x Genomics Xenium <i>In Situ</i> 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.<h4>Results</h4>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; <i>p</i> < 0.001) and increased adjacency between CD4⁺ T cells and fibroblasts (62.3 ± 4.5% vs. 28.7 ± 3.8% in controls; <i>p</i> < 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 (<i>p</i> < 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 (<i>p</i> < 0.001) and correlated with clinical severity (serum IgE: <i>r</i> = 0.71; SPT wheal diameter: <i>r</i> = 0.65; <i>p</i> < 0.001).<h4>Conclusions</h4>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.