Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma
Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma
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DOI：
10.4049/jimmunol.173.7.4352
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Yu, JS
中科院分区：
文献类型：
--
作者：
Akasaki, Y;Liu, G;Yu, JS
前列腺素E(2)是由环氧合酶-2(COX-2)过表达的肿瘤合成的，已知有助于癌症患者的细胞免疫抑制，但其机制尚不清楚。我们报道了CD11c(+)成熟树突状细胞(DC)吞噬同种异体胶质瘤和自体COX-2过表达的胶质瘤诱导CD4(+)T调节类型1(TR1)的机制。人脑胶质瘤细胞系U-87 mg和原代培养的胶质母细胞瘤细胞(MG-377)过表达COX-2。我们没有检测到IL-10Rpha在这些胶质瘤中的表达，rIL-10也没有抑制它们的COX-2表达。暴露于高表达COX-2的胶质瘤中，可诱导成熟DC过度表达IL-10，降低IL-12p70的产生。这些DC诱导了TR1反应，其特征是CD4(+)T细胞强烈分泌IL-10和转化生长因子-β，而IL-4分泌很少，对混合淋巴细胞有抑制作用。从MG-377患者中分离出的外周CD4(+)T细胞群也主要表现出对MG-377细胞的TR1反应。在DC吞噬COX-2过表达的胶质瘤时，选择性地抑制COX-2可以取消这一调节反应，而是激发Th1活性。稳定表达COX-2的LN-18(LN-18-COX2)细胞也能诱导TR1反应。PGE(2)对LN-18-COX2细胞COX-2的抑制作用是可逆的。综上所述，在局部微环境中对IL-10不敏感的COX-2过度表达的胶质瘤中，PGE(2)的强健水平可能会导致DC分泌高水平的IL-10。这些结果表明，COX-2过表达的肿瘤诱导了TR1反应，该反应是由肿瘤暴露的、IL-10增强的DC介导的。
PGE(2), synthesized by cyclooxygenase-2 (COX-2)-overexpressing tumor, is known to contribute to cellular immune suppression in cancer patients, but the mechanism remains unclear. We report the mechanism of a CD4(+) T regulatory type 1 (Tr1) induction by CD11c(+) mature dendritic cells (DCs) that phagocytose allogeneic and autologous COX-2-overexpressing glioma. A human glioma cell line, U-87MG, and primary cultured glioblastoma cells (MG-377) overexpressed COX-2. We did not detect IL-10Ralpha expression in these gliomas, and rIL-10 did not suppress their COX-2 expression. Exposure to COX-2-overexpressing glioma induced mature DCs to overexpress IL-10 and decreased IL-12p70 production. These DCs induced a Tr1 response,which is characterized by robust secretion of IL-10 and TGF-beta with negligible IL-4 secretion by CD4(+) T cells, and an inhibitory effect on admixed lymphocytes. Peripheral CD4(+) T cell populations isolated from an MG-377 patient also predominantly demonstrated a Tr1 response against MG-377 cells. Selective COX-2 inhibition in COX-2-overexpressing gliomas at the time of phagocytic uptake by DCs abrogated this regulatory response and instead elicited Th1 activity. COX-2 stable transfectants in LN-18 (LN-18-COX2) also induced a Tr1 response. The effect of a COX-2 inhibition in LN-18-COX2 is reversible after administration of PGE(2). Taken together, robust levels of PGE(2) from COX-2-overexpressing glioma, which is unresponsive to IL-10 within the local microenvironment, may cause DCs to secrete high levels of IL-10. These results indicate that COX-2-overexpressing tumors induce a Tr1 response, which is mediated by tumor-exposed, IL-10-enhanced DCs.