Single-cell and spatial profiling reveal cDC2A-CXCL13+CD8+ T-epithelial cell crosstalk and cytotoxicity through TNFRSF9 in cutaneous and mucosal lichen planus

Abstract Lichen planus (LP) is a chronic inflammatory disease of the skin and mucous membranes, marked by T cell infiltration and keratinocyte apoptosis. However, its immune microenvironment remains poorly understood. Using single-cell RNA sequencing, spatial transcriptomics, and proteomics on samples from 28 patients and 18 healthy controls, we identify elevated interferon (IFN) and cytotoxic signatures in CXCL13+CD8+ T cells in both cutaneous and mucosal LP, but not in lichen planopilaris. T cells expressing TNF and IFNG are spatially linked to epithelial cells through ligand-receptor interactions, correlating with inflammation. We identify cDC2A cells as key contributors, proximal to CXCL13+CD8+ T cells, serving as a major source of IL-15. CXCL13+CD8+ T cells express TNFRSF9 (4-1BB), which enhances their cytotoxic responses in the skin. In summary, our data reveal a critical role for cDC2A in driving CXCL13+CD8+ T–epithelial cytotoxicity in cutaneous and mucosal LP through TNFRSF9.