Evidence of the extrathymic development of tyrosinase-related protein-2-recognizing CD8+ T cells with low avidity

The majority of the human tumour‐associated antigens characterized to date are derived from non–mutated self‐proteins. However, nothing is known about the development of autoreactive and tumour‐associated antigen‐recognizing T cells. Tyrosinase‐related protein (TRP)‐2 is a non‐mutated melanocyte differentiation antigen and TRP‐2‐recognizing CD8⁺ T cells are known to show responses to melanoma both in humans and mice. In addition, TRP‐2‐reactive T cells with low avidity have been suggested to be readily induced from the spleen cells of naïve mice. On the other hand, recent reports suggest that self antigen‐reactive CD8⁺ T cells can be positively selected in the periphery. In this study, we tested the possibility that TRP‐2‐reactive CD8⁺ T cells in naïve mice could develop via the extrathymic pathway. As a consequence, TRP‐2‐reactive CD8⁺ T cell precursors in naïve C57BL/6 mice were suggested to express both interleukin‐2 (IL‐2) receptor β chain (IL‐2Rβ) and CD44 molecules, in a manner similar to that of extrathymically developed T cells. Furthermore, IL‐2Rβ⁺ CD44⁺ CD8⁺ T cells were detected in the adult thymectomized and bone marrow‐reconstituted mice, and functional TRP‐2‐reactive T cells were generated from their spleen cells. Overall, these results suggest that low avidity CD8⁺ T cells recognizing TRP‐2 can be developed extrathymically.