AIRE polymorphisms induce variable extent of apoptosis on melanoma-specific CD8+ T lymphocytes.

AIRE regulates thymocyte selection by inducing the expression of tissue-restricted self antigens (TRAs) in medullary thymic epithelial cells (mTECs). MAGE antigens are among TRAs regulated by AIRE. Single nucleotide polymorphisms (SNPs) of AIRE gene have been reported in humans but their impact on repertoire selection of tumor antigen-specific T lymphocytes is unknown. We report here that the rs1800522 SNP of human AIRE gene is present in mice and that the relative T or C allelic variants differently regulate MAGEB2 gene expression in mTECs. The C allelic variant, protective in humans against melanoma, induces lower MAGEB2 expression than the T allele. When mouse mTECs bearing the TT genotype were gene targeted to substitute the T with the C allelic variant, the co-culture of wild type or transgenic mTECs with MAGEB2-specific syngeneic T cells induced reduced extent of apoptosis and increased frequency of MAGEB2-specific viable T lymphocytes in T cells cultured with mTECs bearing the CC with respect to the TT genotype. These findings demonstrate that alternative allelic variants of AIRE SNPs may differently modulate the T cell repertoire specific against melanoma cells and subsequently may be linked to a different level of suceptibility to a neoplastic disease such as melanoma.