Kuwabara Jun, Umakoshi Akihiro, Abe Naoki, Sumida Yutaro, Ohsumi Shota, Usa Eika, Taguchi Kana, Choudhury Mohammed E, Yano Hajime, Matsumoto Shirabe, Kunieda Takeharu, Takahashi Hisaaki, Yorozuya Toshihiro, Watanabe Yuji, Tanaka Junya
Department of Gastrointestinal Surgery and Surgical Oncology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Biochem Biophys Res Commun. 2018 Feb 5;496(2):542-548. doi: 10.1016/j.bbrc.2018.01.065. Epub 2018 Jan 12.
CD200 mediates immunosuppression in immune cells that express its receptor, CD200R. There are two CD200 variants; truncated CD200 that lacks the part of N-terminal sequence necessary for CD200R binding (CD200S) and full-length CD200 (CD200L). We established a novel lung metastasis model by subcutaneously transplanting C6 glioma cells into the backs of neonatal Wistar rats. All transplanted rats developed large back tumors, nearly 90% of which bore lung metastases. To compare the effects of CD200S and CD200L on tumor immunity, CD200L (C6-L)- or CD200S (C6-S)-expressing C6 cells were similarly transplanted. The results showed that 100% of rats with C6-L tumors developed lung metastases, while metastases were found in only 44% of rats with C6-S tumors (n = 25). Tumors disappeared in approximately 20% of the C6-S-bearing rats, and these animals evaded death 180 d after transplantation, while all C6-L tumor-bearing rats died after 45 d. Next generation sequencing revealed that C6-S tumors expressed chemokines and granzyme B at much higher levels than C6-L tumors. Flow cytometry revealed that C6-S tumors contained more dead cells and more CD45 cells, including natural killer cells and CD8 lymphocytes. In particular, multiple subsets of dendritic cells expressing CD11c, MHC class II, CD8, and/or CD103 were more abundant in C6-S than in C6-L tumors. These results suggested that CD200S induced the accumulation of multiple dendritic cell subsets that activated cytotoxic T lymphocytes, leading to the elimination of metastasizing tumor cells.
CD200在表达其受体CD200R的免疫细胞中介导免疫抑制作用。CD200有两种变体；截短的CD200（CD200S），其缺乏与CD200R结合所需的N端序列部分，以及全长CD200（CD200L）。我们通过将C6胶质瘤细胞皮下移植到新生Wistar大鼠的背部，建立了一种新的肺转移模型。所有移植的大鼠背部都长出了大肿瘤，其中近90%发生了肺转移。为了比较CD200S和CD200L对肿瘤免疫的影响，将表达CD200L（C6-L）或CD200S（C6-S）的C6细胞进行了类似的移植。结果显示，携带C6-L肿瘤的大鼠中有100%发生了肺转移，而携带C6-S肿瘤的大鼠中只有44%发现有转移（n = 25）。约20%携带C6-S肿瘤的大鼠肿瘤消失，这些动物在移植后180天存活，而所有携带C6-L肿瘤的大鼠在45天后死亡。下一代测序显示，C6-S肿瘤中趋化因子和颗粒酶B的表达水平比C6-L肿瘤高得多。流式细胞术显示，C6-S肿瘤中含有更多的死亡细胞和更多的CD45细胞，包括自然杀伤细胞和CD8淋巴细胞。特别是，表达CD11c、MHC II类、CD8和/或CD103的多个树突状细胞亚群在C6-S肿瘤中比在C6-L肿瘤中更丰富。这些结果表明，CD200S诱导了多个树突状细胞亚群的积累，这些亚群激活了细胞毒性T淋巴细胞，从而导致转移肿瘤细胞的清除。
