109 Bidirectional TGF-beta signaling between CD8+ T cells and melanocytes determines melanocyte death in vitiligo

Vitiligo is an autoimmune skin disease characterized by depigmentation, caused autoreactive IFNg-producing CD8+ T cells (CD8s) that target melanocytes and promote their destruction. Using single-cell RNA sequencing from the of vitiligo patients as well healthy controls, we determined CD8s directly communicate through TGFb signaling, with CD8-specific production TGFb1 melanocyte-specific TGFb2. Broad -omics analysis revealed overall gene expression protein levels are downregulated in lesional compared to skin, promoting inflammatory environment. However, upregulate decrease receptor (TGFbR) blood. While both express receptors for TGFb, signaling primarily reported modulate cell phenotypes induce tolerance, while its role unknown. We found TGFb1/2 inhibited proliferation activated patients, TGFb2 decreased transcription cytotoxic molecules FASLG PRF1. In primary human melanocytes, upregulated genes involved apoptosis support adhesion, functionally induced melanocyte death, which was potentiated exposure IFNg. IFNg also TGFb1-induced death mitigated blocking a small molecule inhibitor. This study implicates bidirectional communication within during vitiligo, use reduce CD8 cytotoxicity thereby “defend” themselves against attack. lesions, may TGFbR escape this regulation “consent” killing decreasing promotes these changes, transitioning state.