Self-Tolerance to the Murine Homologue of a Tyrosinase-derived Melanoma Antigen: Implications for Tumor Immunotherapy

The human tyrosinase-derived peptide Y MDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A * 0201 1 melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide F MDGTMSQV, together with transgenic mice expressing the HLA-A * 0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with recombinant vaccinia virus encoding murine tyrosinase, we detected a robust AADrestricted cytotoxic T lymphocyte (CTL) response to F MDGTMSQV in AAD transgenic mice in which the entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD 1 tyrosinase 1 mice after activation under certain conditions. At least some of these residual CTLs in AAD 1 tyrosinase 1 mice were of high avidity and induced vitiligo upon adoptive transfer into AAD 1 tyrosinase 1 hosts. Collectively, these data suggest that F MDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.