AIRE polymorphism, melanoma-antigen-specific T cell immunity, and susceptibility to melanoma.

AIRE which regulates T cell repertoire is involved in susceptibility to melanoma. Whether this role is mediated by melanoma antigen (MA)-specific T cell immunity is not known. In this study, we have tested this possibility, taking advantage of the structural and functional homology of human AIRE and MAGE with their mouse counterparts. AIRE and MAGEB2 expression was measured by real time PCR in medullary thymic epithelial cells (mTECs) from two strains of C57BL/6 mice bearing selectively one of the two (T or C) allelic variants of rs1800522 AIRE SNP. The extent of apoptosis induced by mTECs in MAGEB2-specific T cells and the susceptibility to in vivo melanoma B16F10 cell challenge were compared in the two mousestrains.
The C allelic variant, protective in humans against melanoma, inducedlower AIRE and MAGEB2 expressionin C57BL/6 mouse mTECsthan the T allele. mTECs from the strain bearing the AIRE CC genotype induced lower extent of apoptosis in MAGEB2-specific syngeneic T cells than mTECs from the strain bearing the TT genotype (P<0.05). Vaccination against MAGEB2 induced higher frequency of MAGEB2-specific CTL and exerted higher protective effect against melanoma development in mice bearing AIRE CC than in those bearing the TT genotype (P<0.05).These findings show that alternative allelic variants of one AIRE SNP may differentially shape the MA-specific T cell repertoire potentially influencing susceptibility to melanoma.