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The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1-3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions ofthe body4-6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.
Vitiligo is an acquired polygenetic autoimmune disease9. Its defining feature is skin depigmentation, in which affected skin is unable to spontaneously recover owing to the activity of auto-reactive CD8+ T cells, which causes a loss of epidermal melanocytes7'8,10-15. Vitiligo affects 0.5% to 2% of the population worldwide16-18. More than 80% of patients with vitiligo have bilateral symmetric patterns of depigmentation across the central body axis, which is classified as non-segmental vitiligo4-6. Previous studies using a mouse model of vitiligo have shown that IFNy is important for T cell-induced depigmentation in skin19-21. Although various studies have proposed underlying mechanisms22-27, the identity of IFNy-responsive cells that mediate this function is largely unknown. Hypotheses about the reason behind the bilateral symmetric patterns that are observed in vitiligo pathology include regional variations in microbiota distribution; the pattern ofantigen expression in melanocytes; and different distributions of neuropeptides released by nerve endings28-32. Despite these studies, the cellular and...