| In the development of tumor immunotherapies, a number of melanoma antigens have been identified as relevant in vivo targets of the immune response. These tumor-associated antigens are most often derived from normal melanocyte differentiation proteins (MDP), and as such, are subject to immunological self-tolerance. However, despite the wide use of these antigens in clinical trials, the impact of tolerance is difficult to assess in humans. Thus, mechanisms responsible for initiating and maintaining CD8 T cell tolerance to these antigens are largely unknown. We, have previously developed a murine model in which we demonstrated that for the MDP, tyrosinase, endogenous expression of this protein profoundly inhibited the ability to elicit CTL responses in vivo. The current work extends those studies and utilizes a newly generated TCR transgenic mouse to establish the basis of tolerance for this clinically relevant antigen. We show that despite expression of tyrosinase transcripts in the thymus, central deletion does not shape the tyrosinase-specific CD8 T cell repertoire. Instead, this endogenously-expressed melanocyte antigen is constitutively presented in both peripheral and mesenteric lymph nodes, leading to abortive activation and deletion of tyrosinase-specific CD8 T cells. Importantly, this antigen is not presented by either radio-sensitive dendritic cells, or by radio-resistant Langerhans cells as predicted by other models of peripheral tolerance. Instead, we find tyrosinase mRNA expression in lymphoid compartments where CD8 T cell deletion occurs. This suggests that direct presentation of tyrosinase by radio-resistant lymph node resident cells is entirely responsible for tolerance to this endogenous melanocyte differentiation antigen. Additionally, we have characterized the development of spontaneous vitiligo in TCR transgenic mice in which the majority of peripheral CD8 T cells express a tyrosinase-specific TCR. We have shown that induction of epidermal vitiligo is a distinct phenomenon from the depigmentation of hair observed in other marine vitiligo models and have proposed a new experimental model in which both additional immunoregulatory mechanisms, and T cell trafficking to the epidermis can be addressed. |
