Cancellation of NKT cell immunosuppression targeting myeloid suppressor cells
Cancellation of NKT cell immunosuppression targeting myeloid suppressor cells
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取消针对骨髓抑制细胞的 NKT 细胞免疫抑制
DOI：
10.2492/inflammregen.29.128
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发表时间：
2009
影响因子：
8.1
通讯作者：
K. Seino
中科院分区：
文献类型：
--
作者：
H. Wada;K. Yanagisawa;K. Seino
CD 1d限制性自然杀伤T（NKT）细胞是一种免疫调节细胞。NKT细胞可被合成糖脂α-半乳糖神经酰胺（α-GalCer）特异性激活。利用某些糖脂如α-GalCer，有望开发出一种新的NKT细胞介导的抗癌治疗策略。然而，已知在人类癌症患者中，NKT细胞对α-GalCer表达一定程度的低反应性。例如，我们已经报道，在胃肠癌患者中，NKT细胞增殖和细胞因子产生受损。我们进一步研究了使用荷癌小鼠诱导对α-GalCer低反应性的机制。在动物研究中，α-GalCer诱导的NKT细胞扩增、细胞因子产生、细胞毒性和体内抗转移作用均显著受损。事实上，α-GalCer可以消除幼稚动物的转移性疾病，但未能保护荷癌小鼠。我们发现，CD 11b + Gr-1+细胞在荷癌小鼠中特别增加，并且是抑制NKT细胞对α-GalCer的必要和充分的。我们还发现，增加的CD 11b + Gr-1+细胞抑制NKT细胞的功能，在一氧化氮介导的方式。为了减少CD 11b + Gr-1+细胞的数量，我们给荷癌小鼠施用了视黄酸。该处理显著减少了CD 11b + Gr-1+细胞的数量，并有效恢复了α-GalCer诱导的NKT细胞应答。这些结果证明了癌症中NKT细胞功能的新特征，并提出了通过抑制CD 11b + Gr-1+细胞功能来增强NKT细胞介导的抗癌免疫应答的新策略。
CD1d-restricted natural killer T (NKT) cells are one of immunoregulatory cells. NKT cells can be specifically activated by a synthetic glycolipid, α-galactosylceramide (α-GalCer). Using some glycolipids such as α-GalCer, it is expected to develop a new NKT cell-mediated therapeutic strategy against cancer. However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to α-GalCer. For example, we have reported that, in gastrointestinal cancer patients, NKT cell proliferation and cytokine production were impaired. We have further examined the mechanism by which hyporesponsiveness to α-GalCer can be induced using cancer-bearing mice. In the animal study, α-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and anti-metastatic effect in vivo were all significantly impaired. In fact, α-GalCer could eliminate metastatic disease in naive animals, but failed to protect cancer-bearing mice. We found that CD11b+ Gr-1+ cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of NKT cells to α-GalCer. We also found that the increased CD11b+ Gr-1+ cells suppressed NKT cell function in a nitric oxide-mediated fashion. To reduce the population of CD11b+ Gr-1+ cells, we administered a retinoic acid to cancer-bearing mice. This treatment significantly reduced the population of CD11b+ Gr-1+ cells and effectively restored α-GalCer-induced NKT cell responses. These results demonstrate a novel feature of NKT cell function in cancer, and suggest a new strategy to enhance NKT cell-mediated anti-cancer immune responses by suppressing CD11b+ Gr-1+ cell functions.
NKT 细胞在免疫系统中的功能作用。
DOI：
--
发表时间：
2004
期刊：
Frontiers in Bioscience 9
影响因子：
--
作者：
Seino K.;et al.
通讯作者：
et al.