Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

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Abstract
Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: Cytotoxic T lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte‐specific T cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan‐A/MART‐1‐specific T lymphocytes nor their status of activation differ significantly. However, by using a tetramer‐based T cell receptor down‐regulation assay, we documented a higher affinity of vitiligo T cells. We calculated that the peptide concentration required for 50% of maximal receptor down‐regulation differed by 6.5‐fold between the two diseases. Moreover, only vitiligo T cells were capable of efficient receptor down‐regulation and IFN‐γ production in response to HLA‐matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan‐A/MART‐1‐specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocyte‐specific cytotoxic responses differs between the two pathologies.