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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.

Original publication

DOI

10.4049/jimmunol.177.5.3055

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

09/2006

Volume

177

Pages

3055 - 3062

Addresses

Henry Wellcome Building of Molecular Physiology, University of Oxford, Oxford, United Kingdom.

Keywords

CD4-Positive T-Lymphocytes, Melanocytes, Animals, Mice, Transgenic, Mice, Vitiligo, Muramidase, Oxidoreductases, Tumor Necrosis Factors, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Antigen, T-Cell, Antigens, CD95, Lymphocyte Activation, Signal Transduction, Autoimmunity, Immune Tolerance, Fas Ligand Protein, Myeloid Differentiation Factor 88