scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in T reg function
- 8 September 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (610), eabd8995
- https://doi.org/10.1126/scitranslmed.abd8995
Abstract
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 (Tregs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg 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.Keywords
This publication has 70 references indexed in Scilit:
- An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiationBMC Genomics, 2012
- A Mouse Model of Vitiligo with Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD8+ T-Cell Accumulation in the SkinJournal of Investigative Dermatology, 2012
- clusterProfiler: an R Package for Comparing Biological Themes Among Gene ClustersOMICS: A Journal of Integrative Biology, 2012
- Interleukin-12 Converts Foxp3+ Regulatory T Cells to Interferon–γ-Producing Foxp3+ T Cells That Inhibit ColitisGastroenterology, 2011
- Interleukin-26: An IL-10-related cytokine produced by Th17 cellsCytokine & Growth Factor Reviews, 2010
- Differentiation of Effector CD4 T Cell PopulationsAnnual Review of Immunology, 2010
- Key Roles for Transforming Growth Factor β in Melanocyte Stem Cell MaintenanceCell Stem Cell, 2010
- The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammationNature Immunology, 2009
- CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistenceThe Journal of Experimental Medicine, 2006
- Normalized cuts and image segmentationIEEE Transactions on Pattern Analysis and Machine Intelligence, 2000