Predominant activation of extrathymic T cells during melanoma development of metallothionein/ret transgenic mice.

Transgenic mice that carried a metallothionein/ret fusion gene (Tg.MT/ret mice) exhibited severe pigmentation in their skin after birth and developed melanomas at adult ages. To learn how the immune system was modulated during melanoma development in these mice, lymphocytes in various organs were examined. An immunofluorescence cell analysis was focused on the simultaneous characterization of T cells of extrathymic and thymic origins and performed at three time points: 6 weeks of age (before melanoma development), 20 weeks (after melanoma development), and 30 weeks (end stage). The number and proportion of extrathymic T cells with TCR of intermediate intensity (i.e., intermediate TCR cells) were markedly increased in the liver over entire periods of life. These intermediate TCR cells constitutively expressed IL-2R beta, contained double-negative CD4-8- cells, and predominated V beta 8+ cells. Such intermediate TCR cells were also abundant among tumor infiltrating lymphocytes. In contrast, an increase in the number and proportion of regular T cells with TCR of bright intensity (i.e., bright TCR cells of thymic origin) was seen at only a limited period in various organs. Rather, at the late phase, thymic atrophy was induced and accompanied with the decrease in the proportion of bright TCR cells in the periphery. These results suggested that extrathymic T cells generated in the liver might play important roles in tumor immunity.