Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma
Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma
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DOI：
10.1371/journal.pone.0122387
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发表时间：
2015-05-08
期刊：
影响因子：
3.7
通讯作者：
Lamb, Lawrence S., Jr.
中科院分区：
文献类型：
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作者：
Beck, Benjamin H.;Kim, Hyunggoon;Lamb, Lawrence S., Jr.
在体外和人/小鼠胶质母细胞瘤异种移植模型中，人γδT细胞是针对神经胶质瘤细胞系的有效效应器，然而，尚未在免疫活性小鼠模型中研究这种效应。在本报告中，我们在同基因WT C57BL/6小鼠中建立了GL261颅内神经胶质瘤，并测量了注射后第10-12天和末期的循环γδT细胞计数、表型、Vγ/γδ库、肿瘤组织病理学、NKG2D配体表达和T细胞侵袭。在肿瘤后第 10-12 天，循环的 γ δ T 细胞短暂增加并上调膜联蛋白 V 表达，随后在末期γ δ T 细胞计数急剧下降。 T 细胞受体库显示，在肿瘤后第 10-12 天或末期，V gamma 1、V gamma 4、V gamma 7 或 V delta 1 亚群与对照组相比没有变化，但 V delta 4 群体在末期有所增加。大约 12% 的 γ δ T 细胞产生 IFN-γ。未检测到产生 IL-17 和 IL-4 的 γ δ T 细胞。 TCR δ(-/-)C57BL/6 小鼠中的肿瘤进展与 WT 小鼠中观察到的相同，表明 γ δ T 细胞对肿瘤既没有发挥调节作用，也没有发挥可持续的细胞毒作用。在肿瘤放置后 15m 接受颅内注射 γδT 细胞的 WT 小鼠显示出局部肿瘤生长抑制的证据，但这不足以赋予相对于未治疗对照的生存优势。综上所述，我们的研究结果表明，在植入同基因 GL261 神经胶质瘤的小鼠中，γδT 细胞早期非特异性增殖，随后被耗尽。 γδT 细胞扩增发生的机制仍然是高级神经胶质瘤环境中导致这种免疫反应的机制进一步研究的课题。
Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneicWT C57BL/6 mice and measured circulating gamma delta T cell count, phenotype, V gamma/gamma delta repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10-12 post-injection and at end stage. Circulating gamma delta T cells transiently increased and upregulated Annexin V expression at post-tumor day 10-12 followed by a dramatic decline in gamma delta T cell count at end stage. T cell receptor repertoire showed no changes in V gamma 1, V gamma 4, V gamma 7 or V delta 1 subsets from controls at post-tumor day 10-12 or at end stage except for an end-stage increase in the V delta 4 population. Approximately 12% of gamma delta T cells produced IFN-gamma. IL-17 and IL-4 producing gamma delta T cells were not detected. Tumor progression was the same in TCR delta(-/-)C57BL/6 mice as that observed in WT mice, suggesting that gamma delta T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of gamma delta T cells 15m following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of gamma delta T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which gamma delta T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma.