Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma.
Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma.
复制标题
DOI：
10.1158/0008-5472.can-09-0266
复制
发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Ansell SM
中科院分区：
文献类型：
--
作者：
Yang ZZ;Novak AJ;Ziesmer SC;Witzig TE;Ansell SM
使用b细胞非霍奇金淋巴瘤患者的活检标本，我们观察到TH17细胞的频率明显较低，包括肿瘤微环境中未检测到产生白细胞介素(IL)-17细胞的几个样本。我们发现，在没有淋巴瘤B细胞的情况下，用IL-1β/IL-6或脂多糖（LPS）处理可以增强CD4+ T细胞中IL-17的表达，当CD4+ T细胞与淋巴瘤B细胞共培养时，这种增强作用减弱。通过抗cd70或抗cd80 /86抗体阻断CD27-CD70或CD28-CD80/86相互作用，恢复lps介导的诱导IL-17在与淋巴瘤B细胞共培养的CD4+ T细胞中的表达。由于淋巴瘤B细胞的一个子集表达IL-2，并且考虑到IL-2信号在调节性T （Treg）细胞的发育中至关重要，我们测试了IL-2信号在TH17细胞发育中的作用。我们发现用抗IL-2抗体阻断IL-2信号通路显著抑制Foxp3在CD4+ T细胞中的表达。相反，IL-2信号通路的中断上调了CD4+ T细胞中IL-17的表达，恢复了淋巴瘤介导的IL-17产生细胞的下调。此外，LPS或CpG-A对Treg细胞活性的逆转导致il -17生成细胞的增强。综上所述，我们的研究表明，淋巴瘤B细胞在扭曲Treg和TH17细胞之间的平衡，从而建立深度抑制肿瘤微环境方面发挥了重要作用。
Using biopsy specimens from patients with B-cell non-Hodgkin’s lymphoma, we observed a significantly low frequency of TH17 cells, including several samples with no detectable amount of interleukin (IL)-17–producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1β/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 express ion in CD4+ T cells and this enhancement was attenuated when CD4+ T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4+ T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (Treg) cells, we tested the role of IL-2 signaling in TH17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4+ T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4+ T cells and restored lymphoma-mediated down-regulation of IL-17–producing cells. Furthermore, the reversal of Treg cell activity by LPS or CpG-A resulted in an enhancement of IL-17–producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between Treg and TH17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment.