HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation.
HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation.
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尽管表型激活，HIV诱导的I型干扰素和色氨酸分解代谢驱动T细胞功能障碍。
DOI：
10.1371/journal.pone.0002961
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发表时间：
2008-08-13
期刊：
影响因子：
3.7
通讯作者：
Shearer GM
中科院分区：
文献类型：
--
作者：
Boasso A;Hardy AW;Anderson SA;Dolan MJ;Shearer GM
人类免疫缺陷病毒（HIV）感染的特征是功能受损和T淋巴细胞的慢性活化，其原因在很大程度上无法解释。我们培养的外周血单核细胞（PBMC）从艾滋病毒未感染的捐助者在存在或不存在的艾滋病毒。HIV暴露增加了CD 4和CD 8 T细胞上活化标志物CD 69和CD 38的表达。由HIV激活的浆细胞样树突状细胞（pDC）产生的IFN-α/β是上调CD 69和CD 38所必需和充分的，因为HIV诱导的效应被IFN-α/β受体阻断剂抑制，并被重组IFN-α/β模拟。来自HIV暴露的PBMC的T细胞在T细胞受体刺激后表现出增殖减少，部分被1-甲基色氨酸阻止，1-甲基色氨酸是HIV活化的pDC表达的免疫抑制酶吲哚胺（2，3）-双加氧酶（IDO）的竞争性抑制剂。HIV诱导的IDO通过将CD 4 T细胞阻滞在G1/S期而抑制其增殖，通过下调共刺激受体CD 28而阻止CD 8 T细胞进入细胞周期。最后，由IDO激活的应激反应的标志物CHOP的表达在体外T细胞中被HIV上调，并且在来自HIV感染患者的T细胞中增加。我们的数据提供了HIV诱导的T细胞失调的体外模型，并支持这样的假设，即pDC的活化伴随着HIV感染期间T细胞表型活化和T细胞增殖能力的抑制。
Infection by the human immunodeficiency virus (HIV) is characterized by functional impairment and chronic activation of T lymphocytes, the causes of which are largely unexplained. We cultured peripheral blood mononuclear cells (PBMC) from HIV-uninfected donors in the presence or absence of HIV. HIV exposure increased expression of the activation markers CD69 and CD38 on CD4 and CD8 T cells. IFN-α/β, produced by HIV-activated plasmacytoid dendritic cells (pDC), was necessary and sufficient for CD69 and CD38 upregulation, as the HIV-induced effect was inhibited by blockade of IFN-α/β receptor and mimicked by recombinant IFN-α/β. T cells from HIV-exposed PBMC showed reduced proliferation after T cell receptor stimulation, partially prevented by 1-methyl tryptophan, a competitive inhibitor of the immunesuppressive enzyme indoleamine (2,3)-dioxygenase (IDO), expressed by HIV-activated pDC. HIV-induced IDO inhibited CD4 T cell proliferation by cell cycle arrest in G1/S, and prevented CD8 T cell from entering the cell cycle by downmodulating the costimulatory receptor CD28. Finally, the expression of CHOP, a marker of the stress response activated by IDO, was upregulated by HIV in T cells in vitro and is increased in T cells from HIV-infected patients. Our data provide an in vitro model for HIV-induced T cell dysregulation and support the hypothesis that activation of pDC concomitantly contribute to phenotypic T cell activation and inhibition of T cell proliferative capacity during HIV infection.
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影响因子：
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