Inhibition of activated/memory (CD45RO+) T cells by oxidative stress associated with block of NF-κB activation
Inhibition of activated/memory (CD45RO+) T cells by oxidative stress associated with block of NF-κB activation
复制标题
DOI：
10.4049/jimmunol.167.5.2595
复制
发表时间：
2001-09-01
影响因子：
4.4
通讯作者：
Kiessling, R
中科院分区：
文献类型：
--
作者：
Malmberg, KJ;Arulampalam, V;Kiessling, R
癌症患者的免疫反应受损与氧化应激有关。因此，活化的肿瘤浸润巨噬细胞或粒细胞释放的活性氧水平升高可能构成有效的癌症免疫治疗的障碍。在这项研究中，我们研究了暴露于低水平氧化应激的 T 细胞的功能后果和分子事件。我们观察到，在 HLA-A*0201 限制性流感肽和非特异性受体交联刺激下，人 PBMC 的细胞因子产生在暴露于微摩尔水平的 H2O2 后减少。通过 IFN-γ 释放测量的功能损伤发生得更早，并且外源添加的 H2O2 剂量比诱导细胞凋亡所需的剂量更低。这表明存在一个氧化应激剂量窗口，导致 T 细胞在不发生细胞凋亡的情况下无反应。 H2O2 诱导的 Th1 细胞因子的减少主要在记忆/效应 (CD45RO(+)) T 细胞中观察到，并且与 NF-κB 激活的阻断相关。与 IFN-γ、TNF-α 和 IL-2 相比，低剂量 H2O2 对 IL-10 产生的影响更为深远。 H2O2 对 IL-10 产生的影响在记忆/激活 T 细胞和初始 T 细胞之间没有显着差异。这些观察结果表明，Th1 和 Th2 细胞因子在氧化应激条件下受到不同的调节。总而言之，这些发现可以解释为什么在肿瘤环境中发现的经历 Ag 的 CD45RO(+) T 细胞在功能上受到抑制。
Impaired immune responses in cancer patients have been associated with oxidative stress. Increased levels of reactive oxygen species released from activated, tumor-infiltrating macrophages or granulocytes may therefore constitute a hurdle for effective immunotherapy against cancer. In this study, we investigated functional consequences and molecular events in T cells exposed to low levels of oxidative stress. We observed that cytokine production of human PBMC, upon stimulation with an HLA-A*0201-restricted influenza peptide and nonspecific receptor cross-linking, was reduced after exposure to micromolar levels of H2O2. Functional impairment as measured by IFN-gamma release occurred earlier and at lower doses of exogenously added H2O2 than required to induce apoptosis. This suggests that there is a dose window of oxidative stress leading to T cell unresponsiveness in the absence of apoptosis. The reduction of Th1 cytokines, induced by H2O2, was predominantly observed in memory/effector (CD45RO(+)) T cells and correlated with a block in NF-kappaB activation. IL-10 production was more profoundly influenced by low doses of H2O2 than IFN-gamma, TNF-alpha, and IL-2. The influence of H2O2 on production of IL-10 was not significantly different between memory/activated and naive T cells. These observations suggest that Th1 and Th2 cytokines are differently regulated under conditions of oxidative stress. Taken together, these findings may explain why Ag-experienced, CD45RO(+), T cells found in the tumor milieu are functionally suppressed.