Development of spontaneous vitiligo in human tyrosinase reactive co-receptor independent TCR transgenic mice (60.11)

Abstract

Abstract Vitiligo is an autoimmune disease of the skin presenting with progressive depigmentation in approximately 0.5% of the population worldwide. Traditionally, vitiligo has been ascribed to a combination of genetic, neurologic and immune deficiencies. However, limited animal models for the disease have hampered its understanding. Clinical trial targeting melanoma has shown that destruction of melanocytes in the skin could be correlated to the presence of auto reactive T cells against melanoma-associated antigen. To gain insight into the crucial involvement of immune system in the development of autoimmune vitiligo, we generated TCR transgenic mice (h3TA2) using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient. These h3TA2 transgenic mice develop spontaneous hair depigmentation that progressed with age. Strikingly, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells in h3TA2 mice. Further our data shows that development of vitiligo in these transgenic mice strongly depends on IFN-gamma as genetic ablation of IFN-gamma controls the disease, whereas CXCR3, TNF-alpha and perforin are dispensable. Our data suggest that IFN-gamma ablation controls development of T cell mediated spontaneous vitiligo and provides a model for testing other therapeutic modalities.