Single-cell and spatial profiling reveals a pathogenic cDC2A-CXCL13+ CD8+ T-epithelial cell communication network in lichen planus

Summary: Abstract Body: Lichen planus (LP) is a chronic inflammatory disease that primarily impacts the skin and mucous membranes. While cutaneous LP is histologically characterized by T cell infiltration and keratinocyte apoptosis, the immune microenvironment and molecular dysregulation underlying LP and its clinical subtypes remain poorly defined. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics to analyze samples from 45 patients, including 15 cutaneous lichen planus (CLP) with 9 matching healthy control skin samples, 6 lichen planopilaris (LPP) with 5 matching healthy scalp controls, and 6 mucosal lichen planus (MLP) with 4 healthy control mucosa samples. We identified increased cytotoxic and interferon (IFN)-response signatures localizing to CXCL13+ CD8+ T cells in LP and MLP, while these signatures were absent in LPP. The CXCL13+ CD8+ T cell communication network involved production of TNF and IFNy, spatially connected by ligand receptor interactions to epithelial cells, accounting for the robust epithelial damage in both CLP and MLP. CLP and MLP, but not LPP, were characterized by predominant transcriptional dysregulation of type I & II IFN downstream genes, including CXCL9, CXCL10, CXCL11 and IFI44L. Notably, we also identified a central role for cDC2A cells, which were abundant in CLP and MLP and spatially proximate to CXCL13+ CD8+ T cells, in fueling their cytotoxic activity. In summary, our data provide novel and comprehensive insights into the pathogenesis of LP across its major clinical subtypes and highlight the central role of cDC2A-CXCL13+ CD8+ T-epithelial cell crosstalk in CLP and MLP. Rundong Jiang¹, Rachael Bogle¹, Joseph Kirma¹, Jennifer Fox¹, Michelle Kahlenberg¹, Georg Martiny-Baron², Till Roehn², Lam C. Tsoi¹, Ben Roediger², Johann E. Gudjonsson¹ 1. University of Michigan, Ann Arbor, MI, United States. 2. Novartis Pharma AG, Basel, Switzerland. Adaptive and Auto-Immunity