Melanocytic nevi are benign proliferations of pigment cells that can occasionally develop into melanomas. There is a significant correlation between increased nevus numbers and melanoma development. Our previous reports revealed that DMBA and TPA induced dysplastic nevi in C3H/HeN mice, with a potential to transform into melanomas. In order to understand the immune mechanisms behind this transformation, we applied increasing DMBA doses followed by TPA to the skin of C3H/HeN mice. We observed that increased doses of DMBA correlated well with increased numbers of nevi. The increased DMBA dose induced diminished immune responses and promoted the expansion of regulatory T cells that resulted in increased IL-10 and reduced IFNγ levels. Mice with increased nevus numbers had loss of p16 expression. These mice had increased migration of melanocytic cells to lymph nodes and a greater percent of lymph nodes produced immortalized melanocytic cell lines. DMBA-induced immunosuppression was lost in CD4KO mice. Lymphocytes in the CD4KO mice produced less IL-10 than CD8KO mice. Further, CD4KO mice had significantly reduced nevus numbers and size compared with wild type and CD8KO mice. These results suggest that regulatory T cells play a vital role in the incidence of nevi and their progression to melanoma.

中文翻译：

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调节性 T 细胞在预防小鼠黑色素细胞痣和黑色素瘤中发挥重要作用

黑素细胞痣是色素细胞的良性增殖，偶尔会发展成黑色素瘤。痣数量增加与黑色素瘤发展之间存在显着相关性。我们之前的报告显示，DMBA 和 TPA 在 C3H/HeN 小鼠中诱导发育不良痣，并有可能转化为黑色素瘤。为了了解这种转变背后的免疫机制，我们在 C3H/HeN 小鼠的皮肤上应用了增加 DMBA 剂量，然后是 TPA。我们观察到 DMBA 剂量的增加与痣数量的增加密切相关。增加的 DMBA 剂量会导致免疫反应减弱并促进调节性 T 细胞的扩增，从而导致 IL-10 增加和 IFNγ 水平降低。痣数量增加的小鼠失去了 p16 的表达。这些小鼠增加了黑素细胞向淋巴结的迁移，并且更大百分比的淋巴结产生了永生化的黑素细胞系。DMBA 诱导的免疫抑制在 CD4KO 小鼠中消失。CD4KO 小鼠中的淋巴细胞比CD8KO 小鼠产生更少的IL-10。此外，与野生型和 CD8KO 小鼠相比，CD4KO 小鼠的痣数量和大小显着减少。这些结果表明，调节性 T 细胞在痣的发生及其发展为黑色素瘤中起着至关重要的作用。