Induction of IL-17 and nonclassical T-cell activation by HIV-Tat proteinj
Induction of IL-17 and nonclassical T-cell activation by HIV-Tat proteinj
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DOI：
10.1073/pnas.1308673110
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发表时间：
2013-08-13
影响因子：
11.1
通讯作者：
Nath, Avindra
中科院分区：
文献类型：
--
作者：
Johnson, Tory P.;Patel, Karan;Nath, Avindra
慢性免疫激活是抗逆转录病毒疗法（ART）治疗HIV感染的主要并发症，可在大脑中引起破坏性免疫重建炎症综合征（IRIS）。这个群体中T细胞活化的机制还不清楚。我们在IRIS患者的大脑中发现了表达HIV-Tat蛋白和IL-17的单核细胞。达特也存在于ART病毒学控制的个体的CSF中。因此，我们检查了达特蛋白是否可以直接激活T细胞。达特转录失调94个基因，并诱导分泌11种细胞因子，特别是激活IL-17信号通路，支持促炎状态的发展。达特增加T细胞IL-17的转录和分泌。达特通过网格蛋白介导的内吞作用迅速进入T细胞，并定位于细胞质和细胞核。达特通过依赖于血管内皮生长因子受体2和下游次级信号传导途径但不依赖于T细胞受体的非经典途径激活T细胞。然而，T细胞的达特刺激不诱导T细胞增殖，但增加病毒感染性。这项研究通过驱动T细胞活化并促进IRIS病理生理学，证明了达特作为毒力因子的作用。这支持了抗Tat疗法与ART结合的必要性，并确定了多种可靶向的途径来防止Tat介导的T细胞活化。
Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17-expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat's role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.