Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.
Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.
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功能障碍的HIV特异性CD8+ T细胞增殖与caspase-8活性的增加有关，并通过坏死性介导。
DOI：
10.1016/j.immuni.2014.12.011
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发表时间：
2014-12-18
期刊：
影响因子：
32.4
通讯作者：
Walker, Bruce D.
中科院分区：
文献类型：
--
作者：
Gaiha, Gaurav D.;McKim, Kevin J.;Woods, Matthew;Pertel, Thomas;Rohrbach, Janine;Barteneva, Natasha;Chin, Christopher R.;Liu, Dongfang;Soghoian, Damien Z.;Cesa, Kevin;Wilton, Shannon;Waring, Michael T.;Chicoine, Adam;Doering, Travis;Wherry, E. John;Kaufmann, Daniel E.;Lichterfeld, Mathias;Brass, Abraham L.;Walker, Bruce D.
人类免疫缺陷病毒 (HIV) 特异性 CD8+ T 细胞增殖减少是慢性感染的标志，但下降的机制尚不清楚。我们分析了受控和不受控感染患者的抗原刺激的 HIV 特异性 CD8+ T 细胞的基因表达谱，并确定 caspase-8 与功能失调的 CD8+ T 细胞增殖相关。 Caspase-8 活性在进展者的 HIV 特异性 CD8+ T 细胞中上调，与疾病进展和程序性细胞死亡 1 (PD-1) 表达呈正相关，但与增殖呈负相关。此外，进展细胞上调膜相关 caspase-8 活性的能力下降，抗原刺激后坏死细胞死亡增加，这表明程序性细胞死亡途径坏死性凋亡。体外坏死性凋亡阻断可以挽救进展者中 HIV 特异性 CD8+ T 细胞的增殖，沉默坏死性凋亡介质 RIPK3 也是如此。因此，导致 caspase-8 活性上调的慢性刺激通过激活坏死性凋亡和增加细胞死亡，导致 HIV 特异性 CD8+ T 细胞增殖功能失调。
Decreased human immunodeficiency virus (HIV)-specific CD8+ T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8+ T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8+ T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8+ T cell proliferation through activation of necroptosis and increased cell death.
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