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.