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

  • Nat Commun. 2026 Mar 14;17(1):3962. doi: 10.1038/s41467-026-70506-z.
Rundong Jiang  1  2 ,  Rachael Bogle  1 ,  Xianying Xing  1 ,  Joseph Kirma  1 ,  Jennifer Fox  1 ,  Paul W Harms  1  3 ,  Tran Do  1 ,  Allison C Billi  1 ,  J Michelle Kahlenberg  4 ,  Robert L Modlin  5 ,  Rosane Teles  5 ,  Julie West  5 ,  Aaron Mangold  6 ,  Haihan Zhang  7 ,  Martin A Schneider  8 ,  Sandro Bruno  8 ,  Ben Roediger  8 ,  Georg Martiny-Baron  8 ,  Lam C Tsoi  1 ,  Feriel Hacini-Rachinel  8 ,  Till A Röhn  8 ,  Johann E Gudjonsson  9  10  11
Affiliations
  • 1. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • 2. Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.
  • 3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 4. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
  • 5. Department of Dermatology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
  • 6. Department of Dermatology, Mayo Clinic, Scottsdale, AZ, USA.
  • 7. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • 8. Immunology Disease Area, Novartis BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
  • 9. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 10. Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 11. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA. [email protected].
PMID: 41832141 DOI: 10.1038/s41467-026-70506-z
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.