Multi-modal skin atlas associates a multicellular immune-stromal community with altered cornification and T cell expansion in atopic dermatitis [scATAC-seq]

In healthy skin, a cutaneous immune system maintains balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents, but in atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete, including pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells from 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from 4 studies into a comprehensive atlas. Lesional skin comprised a unique immune and stromal multicellular community that included populations of MMP12+ DCs, mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19+ IL4I1+ fibroblasts, and clonally expanded IL13+IL22+IL26+ T cells with overlapping type 2 and type 17 characteristics, connected by multiple inter-cellular positive feedback loops. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD associated with signals from the disease-associated immune compartment. AD GWAS gene expression was enriched in cornified keratinocytes, IL13+IL22+IL26+ T cells, and ILCs, suggesting that epithelial or immune dysfunction can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation. 3mm patient biopsies from healthy donors, non-lesional and lesional biopsies from atopic dermatitis patients or scleroderma patients were enzymatically dissociated and analyzed using 10x Genomics 3' scRNA-seq platform using Chromium 3’- v3 chemistry or 10x Genomics scATAC-seq platform using Chromium ATAC- v1.1 chemistry or 10x Genomics 5' scRNA-seq and VDJ platform using Chromium 5’- v1.1 chemistry. Murine samples were processed the same, but constituted dorsal skin that was either treated with MC903 to induce AD-like skin inflammation or left untreated as control. ***Please note that raw data is to be made available through dbGaP (controlled access) due to human subject privacy concerns***