Butyrophilin 3A/CD277-Dependent Activation of Human γδ T Cells: Accessory Cell Capacity of Distinct Leukocyte Populations
Butyrophilin 3A/CD277-Dependent Activation of Human γδ T Cells: Accessory Cell Capacity of Distinct Leukocyte Populations
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DOI：
10.4049/jimmunol.1600913
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发表时间：
2016-10-15
影响因子：
4.4
通讯作者：
Kabelitz, Dieter
中科院分区：
文献类型：
--
作者：
Nerdal, Patrik Theodor;Peters, Christian;Kabelitz, Dieter
人 V gamma 9V delta 2 T 细胞以嗜丁酸蛋白 3A/CD277 依赖性方式识别微生物 (E)-4-羟基-3-甲基-丁-2-烯基焦磷酸 (HMBPP) 或内源性焦磷酸（异戊烯基焦磷酸 [IPP]）。唑来膦酸 (ZOL) 等氮二膦酸盐可选择性触发 γ δ T 细胞激活，因为它们通过抑制 IPP 合成下游的甲羟戊酸途径来刺激单核细胞中 IPP 的产生。我们对纯化的单核细胞、中性粒细胞和 CD4 T 细胞作为 V gamma 9V delta 2 T 细胞激活的辅助细胞的能力进行了比较分析，以响应三种选择性但机制不同的刺激（ZOL、HMBPP、激动性抗 CD277 mAb）。只有单核细胞支持对所有三种刺激作出反应的 γ δ T 细胞扩增，而中性粒细胞和 CD4 T 细胞均呈现 HMBPP，但在 ZOL 或抗 CD277 mAb 存在的情况下未能诱导 γ δ T 细胞扩增。辅助细胞与相应刺激物的预孵育显示，ZOL 或抗 CD277 mAb 预处理的单核细胞具有有效的 γ δ T 细胞刺激活性，但中性粒细胞没有。与单核细胞相比，ZOL 预处理的中性粒细胞几乎不产生 IPP（如果有的话），并且表达的法呢基焦磷酸合酶水平要低得多。外源性 IL-18 在所有三种刺激下均增强了 γδT 细胞扩增，显着地还对与抗 CD277 mAb 或 HMBPP 预孵育的 CD4 T 细胞和中性粒细胞做出反应。我们的研究揭示了单核细胞和中性粒细胞在人类 γ δ T 细胞辅助功能方面的意外差异，并强调了 IL-18 在驱动 γ δ T 细胞扩增中的重要作用。这些结果可能对基于 γδT 细胞的免疫治疗策略的设计具有影响。
Human V gamma 9V delta 2 T cells recognize in a butyrophilin 3A/CD277-dependent way microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) or endogenous pyrophosphates (isopentenyl pyrophosphate [IPP]). Nitrogen-bisphosphonates such as zoledronic acid (ZOL) trigger selective gamma delta T cell activation because they stimulate IPP production in monocytes by inhibiting the mevalonate pathway downstream of IPP synthesis. We performed a comparative analysis of the capacity of purified monocytes, neutrophils, and CD4 T cells to serve as accessory cells for V gamma 9V delta 2 T cell activation in response to three selective but mechanistically distinct stimuli (ZOL, HMBPP, agonistic anti-CD277 mAb). Only monocytes supported gamma delta T cell expansion in response to all three stimuli, whereas both neutrophils and CD4 T cells presented HMBPP but failed to induce gamma delta T cell expansion in the presence of ZOL or anti-CD277 mAb. Preincubation of accessory cells with the respective stimuli revealed potent gamma delta T cell-stimulating activity of ZOL-or anti-CD277 mAb-pretreated monocytes, but not neutrophils. In comparison with monocytes, ZOL-pretreated neutrophils produced little, if any, IPP and expressed much lower levels of farnesyl pyrophosphate synthase. Exogenous IL-18 enhanced the gamma delta T cell expansion with all three stimuli, remarkably also in response to CD4 T cells and neutrophils preincubated with anti-CD277 mAb or HMBPP. Our study uncovers unexpected differences between monocytes and neutrophils in their accessory function for human gamma delta T cells and underscores the important role of IL-18 in driving gamma delta T cell expansion. These results may have implications for the design of gamma delta T cell-based immunotherapeutic strategies.