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 Differentiation of naïve CD4+ T cells into T helper (Th) cells is a defining event in adaptive immunity. The cytokines and transcription factors that control Th cell differentiation are understood, however it is not known how this process is orchestrated within lymph nodes (LNs). Here we have shown that the CXCR3 chemokine receptor was required for optimal generation of interferon (IFN)-γ secreting Th1 cells in vivo. Using a CXCR3 ligand reporter mouse, we found that stromal cells predominately expressed the chemokine ligand CXCL9 while hematopoietic cells expressed CXCL10 in LNs. Dendritic cell (DC)-derived CXCL10 facilitated T cell-DC interactions in LNs during T cell priming while both chemokines guided intranodal positioning of CD4+ T cells to interfollicular and medullary zones. Thus, different chemokines acting on the same receptor can function locally to facilitate DC-T cell interactions and globally to influence intranodal positioning, and that both functions contribute to Th1 cell differentiation.

Vitiligo is an autoimmune disease of the skin mediated by CD8 T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (T) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired T formation, and IL-15 promotes T function ex vivo. We found that both human and mouse T express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits T production of interferon-γ (IFNγ), and long-term treatment depletes T from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving T.

Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin revealed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients revealed that keratinocytes were the major chemokine-producers throughout the course of disease, and functional studies using a conditional STAT1 knockout mouse revealed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, as topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.