scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.

Vitiligo allies and villains: Vitiligo is an autoimmune skin disease defined by T cell–mediated destruction of melanocytes. Gellatly et al. (p. 0000) used single-cell RNA sequencing (scRNA-seq) to characterize immune cell subsets that are associated with skin lesions in vitiligo. Type 1 cytokine signaling is a key driver of disease progression, and this signaling pathway was also used by regulatory T cells (T_regs) to limit disease in nonlesional skin. CCR5-CCL5 signaling was critical to effector CD8⁺ T cell and T_reg function, and mouse studies showed that disease suppression required CCR5 expression on T_regs. These studies reveal the complex interactions between immune cell subsets that are involved in vitiligo progression and containment. Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8⁺ T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing on affected and unaffected skin from patients with vitiligo, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also found that this pathway was used by regulatory T cells (T_regs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8⁺ T cells and T_regs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on T_regs was required to suppress disease in vivo but not in vitro. CCR5 was not required for T_reg recruitment to skin but appeared to facilitate T_reg function by properly positioning these cells within the skin. Our data provide critical insights into the pathogenesis of vitiligo and uncover potential opportunities for therapeutic interventions. [ABSTRACT FROM AUTHOR]