Selective Destruction of Interleukin 23-Induced Expansion of a Major Antigen-Specific γδ T-Cell Subset in Patients With Tuberculosis
Selective Destruction of Interleukin 23-Induced Expansion of a Major Antigen-Specific γδ T-Cell Subset in Patients With Tuberculosis
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DOI：
10.1093/infdis/jiw511
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发表时间：
2017-02-01
影响因子：
6.4
通讯作者：
Chen, Zheng W.
中科院分区：
文献类型：
--
作者：
Shen, Hongbo;Gu, Jin;Chen, Zheng W.
尚未有感染期间细胞因子信号传导缺陷导致抗原特异性 T 细胞反应丧失的报道。我们假设结核病可以破坏选择性细胞因子的信号传导作用并诱导抗原特异性 T 细胞耗竭。为了检验这一假设，我们进行了机制研究，以检验结核病是否以及如何阻断白细胞介素 23 (IL-23) 和白细胞介素 2 (IL-2) 对主要人类 γ δ T 细胞亚群（磷酸抗原 HMBPP 特异性 V γ 2V δ 2 T 细胞）的信号传导作用。 IL-23和IL-2显着扩增来自潜伏性结核感染受试者的HMBPP刺激的Vγ2Vδ2T细胞，并且IL-2协同IL-23的作用。 IL-23 诱导的 V gamma 2V delta 2 T 细胞扩增涉及 STAT3。令人惊讶的是，结核病患者表现出对 IL-23 诱导的这些细胞扩增的选择性破坏。结核病驱动的 IL-23 信号传导破坏与 STAT3 表达和磷酸化的降低同时发生。有趣的是，STAT3 的损伤与结核病患者的 V gamma 2V delta 2 T 细胞中 microRNA (miRNA) hsa-miR-337-3p 和 hsa-miR-125b-5p 的显着增加有关。 miRNA海绵下调hsa-miR-337-3p和hsa-miR-125b-5p改善了IL-23介导的V gamma 2V delta 2 T细胞的扩增，并恢复了这些细胞产生抗结核细胞因子的能力。这些结果支持了我们的假设，即结核病可以选择性地损害一种细胞因子的作用，同时保留另一种细胞因子的作用，并且可以诱导 T 细胞对相应细胞因子的反应耗尽。
A loss of antigen-specific T-cell responses due to defective cytokine signaling during infections has not been reported. We hypothesize that tuberculosis can destroy signaling effects of selective cytokine(s) and induce exhaustion of antigen-specific T cells. To test this hypothesis, mechanistic studies were performed to examine whether and how tuberculosis blocked interleukin 23 (IL-23) and interleukin 2 (IL-2) signaling effects on a major human gamma delta T-cell subpopulation, phosphoantigen HMBPP-specific V gamma 2V delta 2 T cells. IL-23 and IL-2 significantly expanded HMBPP-stimulated V gamma 2V delta 2 T cells from subjects with latent tuberculosis infection, and IL-2 synergized the effect of IL-23. IL-23-induced expansion of V gamma 2V delta 2 T cells involved STAT3. Surprisingly, patients with tuberculosis exhibited a selective destruction of IL-23-induced expansion of these cells. The tuberculosis-driven destruction of IL-23 signaling coincided with decreases of expression and phosphorylation of STAT3. Interestingly, impairing of STAT3 was linked to marked increases in the microRNAs (miRNAs) hsa-miR-337-3p and hsa-miR-125b-5p in V gamma 2V delta 2 T cells from patients with tuberculosis. Downregulation of hsa-miR-337-3p and hsa-miR-125b-5p by miRNA sponges improved IL-23-mediated expansion of V gamma 2V delta 2 T cells and restored the ability of these cells to produce anti-tuberculosis cytokines. These results support our hypothesis that tuberculosis can selectively impair a cytokine effect while sparing another and can induce exhaustion of T cells in response to the respective cytokine.