title: CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions.
abstract: Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.
authors.affiliation: Henry Wellcome Building of Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lambe
authors.forename: Janson C H
authors.initials: JC
authors.lastname: Leung
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bouriez-Jones
authors.forename: Karlee
authors.initials: K
authors.lastname: Silver
authors.forename: Kimmo
authors.initials: K
authors.lastname: Makinen
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Crockford
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D053222:Fas Ligand Protein; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008544:Melanocytes / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D014820:Vitiligo / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; C421864:hen egg lysozyme; D009113:Muramidase