TRP-2 TCR Transgenic Mice as a Model to Study CD8+ T cell Responses to Melanoma Antigens (50.15)

Abstract

Abstract To study the effects of T cell avidity on tumor immunity and autoimmunity, we have generated mice that bear T cell receptor (TcR) transgenes specific for a peptide from tyrosinase-related protein 2 (TRP-2), a melanosomal enzyme expressed by both normal melanocytes and melanoma cells. We have begun characterizing a founder mouse line derived from an intermediate avidity T cell line, designated clone 37. Interestingly, the clone 37 TcR transgenic (Tg) mice did not develop autoimmune depigmentation despite the presence of TRP-2-reactive T cells in the lymph nodes and systemic expression of TRP-2. These Tg T cells displayed a naïve phenotype (CD44low, CD62hi, CD69neg, and CD25neg) and proliferated upon stimulation in vitro with cognate antigen. No difference in T cell responsiveness or frequency was observed in the development of Clone 37 T cells following bone marrow reconstitution of wild type C57Bl/6 or TRP-2−/− mice. Adoptive transfer of clone 37 TCR Tg cells into C57BL/6 showed that these T cells do not encounter the endogenous TRP-2 antigen as well as a subcutaneous B16/BL6 melanoma tumor (i.e., they are “ignorant”). However, vaccination with TRP-2 peptide-pulsed dendritic cells induced proliferation of these adoptively transferred CD8+ T cells and subsequent migration into subcutaneous B16/BL6 tumors, but did not inhibit progressive tumor growth. Similarly, B16/BL6 tumors grew progressively in clone 37 TCR Tg mice despite the large number of tumor-associated antigen-specific CD8+ T cells. These findings demonstrate the ability of tumors to evade an anti-tumor immune response despite the presence of tumor-specific T cells. Our on-going studies will characterize two additional mouse lines bearing TcR transgenes from high and low avidity T cell clones and study the impact of different T cell avidities on tumor immunity and autoimmunity.