CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions.
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.
Lambe
Teresa
T
Henry Wellcome Building of Molecular Physiology, University of Oxford, Oxford, United Kingdom.
Leung
Janson C H
JC
Bouriez-Jones
Tiphaine
T
Silver
Karlee
K
Makinen
Kimmo
K
Crockford
Tanya L
TL
Ferry
Helen
H
Forrester
John V
JV
Cornall
Richard J
RJ
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*
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