Development of a transgenic mouse with high affinity TCR reactive to human tyrosinase epitope (41.39)

Abstract

Abstract Most tumor-associated antigen epitopes recognized on human melanomas by autologous T lymphocytes are derived from nonmutated self-proteins. Given the belief that T cells bearing high affinity T cell receptor (TCR) would be more effective at targeting self antigens expressed by tumors, understanding tolerance with reference to T cells expressing high affinity TCRs against self-tumor antigens is important for optimizing the anti-tumor T cell response. Thus, using a high affinity TCR isolated from a class-I restricted CD4+ T cells from tumor infiltrating lymphocytes of a patient with metastatic melanoma and reactive to human tyrosinase-derived peptide YMDGTMSQV we developed a novel TCR transgenic mice. Our results show that HLA-A2 restricted TCR passed thymic selection in C57BL/6J (H2-Kb) wild type mice and could be tracked in the periphery. Around 25% of the peripheral CD4+ T cells and more than 75% of the peripheral CD8+ T cells from these TCR transgenic mice expressed functional human tyrosinase TCR. Since tyrosinase is a self-antigen and C57BL/6J mice lack HLA-A2/tyrosinase complexes on cells in their thymus -we developed HLA-A2+TCR+ double transgenic mice by breeding our TCR transgenic mouse and HLA-A2 transgenic mouse strains. Surprisingly, more than 90% of TCR transgenic T cells in the HLA-A2+TCR+ double transgenic mice lacked expression of CD4 or CD8 co-receptors and had CD3+CD4-CD8- phenotype. These double transgenic strains also developed spontaneous autoimmune vitiligo. Thus, our novel TCR transgenic mouse model would allow us to undertake various developmental and translational studies.