Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4+ T-regulatory cells and systemic collapse of antitumour immunity
Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4+ T-regulatory cells and systemic collapse of antitumour immunity
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DOI：
10.1046/j.1365-2567.2001.01279.x
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发表时间：
2001-08-01
期刊：
影响因子：
6.4
通讯作者：
Tokura, Y
中科院分区：
文献类型：
--
作者：
Seo, N;Hayakawa, S;Tokura, Y
我们研究了转化生长因子-β（TGF-β）分泌T调节（Tr）细胞和抗B16黑色素瘤免疫之间的关系，并研究了在肿瘤部位表达的早期细胞因子与Tr细胞生成的相关性。皮下注射（s.c.）接种B16肿瘤细胞。Tr细胞由两个群体组成，这两个群体被称为T辅助3（Th 3）和Tr 1细胞。B16浸润Tr细胞以TGF-β依赖性方式强烈抑制B16特异性T辅助1（Th 1）细胞的产生，并被认为抑制CTL的有效产生。此外，与未处理的小鼠相比，在由培养的B16浸润Tr细胞过继转移的小鼠中B16细胞显著进展。这些Tr细胞产生TGF-β的能力受到在B16肿瘤早期发展过程中病灶内注射的中和性抗IL-10和部分抗IL-4单克隆抗体（mAb）的阻碍，这种治疗显著减弱了B16的生长。此外，重组小鼠IL-10在早期肿瘤部位的病灶注射导致B16肿瘤的剧烈进展。这些结果提供的证据表明，Tr细胞，属于T辅助细胞3/T-调节1（Th 3/Tr 1）型，在B16荷瘤宿主的T辅助细胞2（Th 2）细胞因子，主要是IL-10（产生于早期肿瘤病变）的影响下被激活，并且这种调节性T细胞群作为抗B16免疫的抑制剂发挥作用。
We investigated the relationship between transforming growth factor-beta (TGF-beta)-secreting T-regulatory (Tr) cells and anti-B16 melanoma immunity, and studied the association of early cytokines expressed at tumour sites with the generation of Tr cells. A large number of CD4(+) Tr cells producing interleukin (IL)-4, IL-10 and TGF-beta accumulated with functionally depressed CD8(+) cytotoxic T lymphocytes (CTLs) at tumour sites on day 20 after subcutaneous (s.c.) inoculation of B16 tumour cells. Tr cells consisted of two populations, which were termed T helper 3 (Th3) and Tr1 cells. B16-infiltrating Tr cells strongly inhibited the generation of B16-specific T helper 1 (Th1) cells in a TGF-beta -dependent manner and were assumed to suppress effective generation of CTLs. In addition, B16 cells markedly progressed in mice transferred adoptively by the cultured B16-infiltrating Tr cells compared with untreated mice. The capacity of these Tr cells to produce TGF-beta was hampered by neutralizing anti-IL-10 and partly anti-IL-4 monoclonal antibodies (mAbs) injected intralesionally during the early development of B16 tumours, and this treatment markedly attenuated B16 growth. Furthermore, a lesional injection of recombinant mouse IL-10 at an early tumour site resulted in the vigorous progression of B16 tumours. These results provide evidence that Tr cells, belonging to the T helper 3/T-regulatory 1 (Th3/Tr1) type, are activated in B16-bearing hosts under the influence of T helper 2 (Th2) cytokines, mainly IL-10 (produced at early tumour lesions), and that this regulatory T-cell population functions as a suppressor of anti-B16 immunity.