Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis

In atopic dermatitis (AD), skin barrier and immune dysfunction result in chronic tissue inflammation, yet our understanding of the tissue ecosystem remains incomplete. Here, we generate a multi-modal census of 280,518 cells from whole skin tissue samples from 17 adults, including 11 AD patients, integrating it with 430,186 cell profiles from four previous studies into a comprehensive human skin cell atlas. Reconstruction of keratinocyte differentiation revealed disrupted cornification in AD associated with signals from an immune and stromal multicellular community - comprising MMP12⁺ and migratory dendritic cells (DCs), cycling innate lymphoid cells (ILC), natural killer cells, inflammatory CCL19⁺ IL4I1⁺ fibroblasts, and clonally expanded IL13⁺IL22⁺IL26⁺ T cells connected by intercellular feedback loops predicted to impact community assembly. Subsets from this community, along with disrupted cornified keratinocytes, were enriched in GWAS, suggesting that dysfunction in this communication network may initiate AD. Our work highlights disease-associated cell subsets and interactions in chronic skin inflammation.