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* Henry Wellcome Building of Molecular Physiology, University of Oxford, Oxford, United Kingdom; and
Department of Ophthalmology, University of Aberdeen, Aberdeen, United Kingdom
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust.
2 T.L. and J.C.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Richard J. Cornall, Henry Wellcome Building of Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, U.K. E-mail address: richard.cornall{at}ndm.ox.ac.uk
4 Abbreviations used in this paper: TRP, tyrosinase-related protein; FasL, Fas ligand; HEL, hen egg lysozyme; mHEL, membrane-bound HEL; DC, dendritic cell; VKH, Vogt-Koyanagi-Harada; Treg, regulatory T.
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