Single-cell transcriptomic profiling of halo nevi and normal nevi reveals CD8+ T cell activation in melanocytic autoimmunity.

Halo nevus is an autoimmune skin disorder characterized by autoreactive CD8+ T cells that target and destroy melanocytes, resulting in a depigmented perilesional halo. Yet the upstream triggers of this activation remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) on halo nevi and normal nevi, identifying ten canonical skin cell types and five melanocyte subclusters. Integrated scRNA-seq and immunofluorescence staining revealed that halo nevi, unlike normal nevi, exhibit robust infiltration of activated, type II interferon-responsive CD8+ T cells. Among melanocyte subclusters, one subset (Cluster 3) showed pronounced upregulation of antigen-presenting molecules, interferon-stimulated genes, and chemokines. Comparative analyses further demonstrated that melanocytes in halo nevi increased oxidative phosphorylation, interferon-driven pathways, and antigen processing and presentation. Together, these data provide single-cell transcriptional atlas of halo nevi versus normal nevi, reveal melanocyte-intrinsic and immune-mediated mechanisms underlying autoimmune melanocyte destruction, and highlight pathogenic pathways shared with vitiligo that may inform the development of targeted therapies.