Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no FDA-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8+ T cells in the skin and blood, which are directly responsible for melanocyte destruction. Here we report that gene expression in lesional skin from vitiligo patients reveals an IFN-γ-specific signature, including the chemokine CXCL10. CXCL10 is elevated in both vitiligo patient skin and serum and CXCR3, its receptor, is expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we employed a mouse model of disease that also exhibits an IFN-γ-specific gene signature, expression of CXCL10 in the skin, and upregulation of CXCR3 on antigen-specific T cells. Mice that receive Cxcr3−/− T cells develop minimal depigmentation, as do mice lacking Cxcl10 or treated with CXCL10 neutralizing antibody. CXCL9 promotes autoreactive T cell global recruitment to the skin but not effector function while, in contrast, CXCL10 is required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo, and thereby support inhibiting CXCL10 as a targeted treatment strategy.

SUMMARY How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of High Mobility Group box (HMG) transcription factors, SOX4, SOX13, TCF1 and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46+ ILCs and restrained cytokine production by Lymphoid Tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins.

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Vitiligo is an autoimmune disease characterized by patchy, depigmented lesions of the skin. The disease is mediated by autoreactive CD8 + T cells that destroy melanocytes. To investigate signaling networks in the skin that lead to this patchy melanocyte destruction, we used a modified suction blistering technique to isolate cells directly from lesional skin and subjected them to single-cell RNA-sequencing. We sequenced cells from both lesional and non-lesional skin in six vitiligo subjects with active disease as well as six healthy controls. We identified multiple cell populations, including melanocytes, keratinocytes, Langerhans cells and immune cells using unbiased differential gene analysis to cluster over 18,000 cell transcriptomes. Moreover, keratinocytes clustered based on differential expression of keratin family members, identifying basal and suprabasal subpopulations. We found an IFN-g signature and elevated CD8 + T cell number in vitiligo lesions, which is consistent with previous findings by our group and others. We also identified CXCR6 and CXCL16, which were recently hypothesized to play a role in vitiligo, in addition to 87 other ligand-receptor pairs that may also help to promote disease progression. Intriguingly, Langerhans cells may play a more active role in vitiligo as they actively express many genes that have known risk alleles. Overall, single-cell RNA-sequencing of cells from blister fluid provides robust data that confirms many previous findings, and adds additional layers of information missed by conventional studies. This level of resolution will yield powerful insight into the identification of novel drug targets in previously unknown pathological signaling pathways in vitiligo and other diseases of the skin. 104IFNg and fas ligand are required for melanocyte destruction in a mouse model of vitiligo Autoreactive CD8 + T cells are responsible for the selective destruction of melanocytes in vitiligo. Previous studies by our group and others demonstrated that IFNg-induced chemokines are required for T cell recruitment into the skin and progression of vitiligo. To determine the mechanism of melanocyte killing by autoreactive T cells in our mouse model of vitiligo, we decided to test the role of known CD8 effector molecules. We found that disease severity and T cell accumulation in the skin was reduced in mice receiving adoptive transfer of either IFNg -/or Fas ligand (FasL) -/autoreactive T cells; however, perforin was dispensable. We did not observe defects in expansion or migration any of the transferred T cells. Co-injections of 50:50 mixed KO T cells with WT T cells rescued vitiligo scores, but did not achieve the same level of disease as mice injected only with WT T cells. Intriguingly, FasL -/and IFNg -/-T cells accumulated in greater numbers in the skin than co-injected WT T cells, suggesting that IFNg and Fas Ligand are required locally in the skin to cause disease. To determine if IFNg has a direct cytotoxic effect on melanocytes, we selectively deleted IFNgR from melanocytes using...

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Alopecia areata (AA) is an inflammatory disease in which autoreactive CD8+ T cells attack the hair follicle (HF) and result in non-scarring alopecia. Previous work from our lab, using both human samples and the graft-induced C3H/HeJ mouse model, established that CD8+ NKG2D+ T cells are the major pathogenic drivers of AA. However, the role of other immune cell types in AA such as regulatory T cells (Tregs), non-Treg CD4+ T cells, and myeloid lineages have not been fully defined. To investigate the complex immune environment underlying AA, we performed single cell RNA-sequencing (scRNAseq) of CD45+ immune cells in skin harvested from affected and unaffected mice. We also performed antibody-based depletion of major immune cell populations to functionally interrogate their role in disease onset, in which 7-week-old C3H/HeJ mice were treated with antibodies one week prior to disease induction via engraftment, followed by continued antibody treatment for two weeks. Consistent with our previous work, scRNAseq revealed a massive expansion of CD8+ T cells in AA, and depletion of CD8+ T cells resulted in complete disease prevention. Non-Treg CD4+ T cells comprised a minor population in our dataset, and accordingly, their depletion resulted in only a slight delay in disease onset with the graft model. Depletion of other minor cell types in our dataset, such as gd-T cells, NK cells, and B cells, had no effect on the kinetics