Mechanisms of Spatial and Temporal Development of Autoimmune Vitiligo in Tyrosinase-Specific TCR Transgenic Mice

Abstract

Generalized vitiligo is thought to have an autoimmune etiology and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation Ag. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase. These animals develop vitiligo with strikingly similar characteristics to the human disease. Vitiligo develops temporally and spatially, with juvenile lesions forming bilaterally in head and facial areas, and only arising later in the body of adult animals. Vitiligo is entirely dependent on CD8 T cells, whereas CD4 T cells exert a negative regulatory effect. Importantly, CD8 T cells can be pervasively present in the skin in the steady state without inducing vitiligo in most areas. This points to developmental differences in melanocyte susceptibility and/or immunological effector mechanisms over time, or in different body locations. Disease is strongly dependent on both IFN-γ and CXCR3, whereas dependence on CCR5 is more limited, and both CCR4 and perforin are dispensable. Genetic ablation of CXCR3 or IFN-γ also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point toward possible therapeutic interventions.

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

“…Cxcr3−/− T cells were impaired in their ability to induce depigmentation (Figure 4A & B) and failed to accumulate in the skin (Figure 4C), despite normal numbers within the skin-draining lymph nodes (Figure 4D). This pattern is similar to that following treatment with IFNγ neutralizing antibody (26), and supports the observation that Cxcr3−/− TCR transgenic host mice are protected from vitiligo in a separate mouse model of hair depigmentation (33). In order to quantify the decreased efficiency of Cxcr3−/− T cell migration to the skin within the same host, we adoptively transferred equal numbers of CFP + WT PMEL T cells and GFP + WT or Cxcr3−/− PMEL T cells into hosts and measured their total numbers in the skin and skin-draining lymph nodes 5 weeks after transfer using flow cytometry.…”

“…Previous studies, including ours, reported that interfering with IFNγ prevents the onset of depigmentation in various mouse models of vitiligo, including genetic deficiency or antibody neutralization (26, 33). However successful treatment strategies should be able to reverse established disease through repigmentation, rather than simply prevent it.…”

Melanocyte-specific CD8+ T cells are associated with epidermal depigmentation in a novel mouse model of vitiligo

“…Previous studies in mouse models of vitiligo have demonstrated that the development of vitiligo requires IFN-γ production by CD8 + T cells [13], and local IFN-γ release in the lesion promotes further recruitment of melanocytespecific CD8…”

A mouse model of vitiligo induced by monobenzone

“…Existing mouse models of vitiligo are generally established through specifically expressing exogenic protein in skin melanocytes, leading to the destruction of the melanocytes by CD8 + CTL targeting the exogenic antigen (9)(10)(11)(12). As a consequence, these vitiligo models do not authentically represent the activation mechanism of autoimmune CD8 + T cells in human vitiligo.…”