Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway
Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway
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DOI：
10.1128/jvi.01475-09
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发表时间：
2010-01-01
影响因子：
5.4
通讯作者：
Chakrabarti, Lisa A.
中科院分区：
文献类型：
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作者：
Juffroy, Olivier;Bugault, Florence;Chakrabarti, Lisa A.
白细胞介素7 (IL-7) 在控制初始和长期记忆CD4(+) T 细胞的稳态中发挥着核心作用。为了更好地了解人类免疫缺陷病毒（HIV）如何扰乱CD4（+）T细胞稳态，我们对来自病毒血症和有效治疗的患者的CD4（+）T细胞亚群中的IL-7R表达、IL-7结合以及IL-7依赖性早期和晚期信号转导事件进行了详细分析。 HIV感染对IL-7受体（IL-7R）链的表达产生不同程度的影响，记忆亚群中IL-7Rα/CD127表达减少，所有CD4+T细胞中γc/CD132表达增加。这导致初始区室中IL-7结合得以保留，而病毒血症患者记忆区室中IL-7结合减少。因此，通过pSTAT5诱导测量，响应IL-7的细胞信号传导百分比在记忆亚群中减少，包括传统的CD4(+) T细胞和调节性T细胞。然而，通过 pSTAT5 荧光强度测量，每个反应细胞的 pSTAT5 诱导水平在病毒血症患者的所有初始和记忆 CD4(+) T 细胞亚群中均有所增加。 pSTAT5 的基础水平也增加，表明 JAK/STAT5 途径的组成型激活。通过 Bcl-2、CD25 和 Foxp3 诱导测量的 IL-7 功能反应在病毒血症患者 CD4+ T 细胞中受损，表明慢性激活导致 STAT5 信号通路下游缺陷。因此，HIV 感染会扰乱受体结合和信号传导步骤中的 IL-7 反应，这可能会损害 CD4(+) T 细胞库的再生能力，并可能导致 CD4(+) T 细胞耗竭。
Interleukin-7 (IL-7) plays a central role in controlling the homeostasis of both naive and long-term-memory CD4(+) T cells. To better understand how human immunodeficiency virus (HIV) perturbs CD4(+) T-cell homeostasis, we performed a detailed analysis of IL-7R expression, IL-7 binding, and IL-7-dependent early and late signaling events in CD4(+) T-cell subsets from viremic and efficiently treated patients. HIV infection differentially affected the expression of IL-7 receptor (IL-7R) chains, with decreases in IL-7R alpha/CD127 expression in the memory subset and increases in gamma c/CD132 expression in all CD4(+) T cells. This resulted in preserved IL-7 binding in the naive compartment and decreased IL-7 binding in the memory compartment of viremic patients. Accordingly, the percentages of cells signaling in response to IL-7, as measured by pSTAT5 induction, were decreased in memory subsets, including conventional CD4(+) T cells and regulatory T cells. However, the levels of pSTAT5 induction per responding cell, as measured by pSTAT5 fluorescence intensity, were increased within all naive and memory CD4(+) T-cell subsets of viremic patients. The basal level of pSTAT5 was also increased, indicating a constitutive activation of the JAK/STAT5 pathway. IL-7 functional responses, as measured by Bcl-2, CD25, and Foxp3 induction, were impaired in viremic patient CD4(+) T cells, suggesting that chronic activation led to downstream defects in the STAT5 signaling pathway. Thus, HIV infection perturbs IL-7 responses at both receptor binding and signaling steps, which likely compromises the regenerative capacity of the CD4(+) T-cell pool and may contribute to CD4(+) T-cell depletion.