T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.
T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.
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DOI：
10.1371/journal.ppat.1004251
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发表时间：
2014-07
期刊：
影响因子：
6.7
通讯作者：
Karlsson AC
中科院分区：
文献类型：
--
作者：
Buggert M;Tauriainen J;Yamamoto T;Frederiksen J;Ivarsson MA;Michaëlsson J;Lund O;Hejdeman B;Jansson M;Sönnerborg A;Koup RA;Betts MR;Karlsson AC
CD8 + T细胞耗竭是慢性HIV感染的一个主要特征。两种调控CD8 + T细胞分化的关键转录因子T - bet和Eomesodermin（Eomes）先前在小鼠中已被证明部分通过直接调节PD - 1来差异调节T细胞耗竭。在此，我们研究了在慢性和接受治疗的HIV感染中，这些转录因子与几种抑制性受体（PD - 1、CD160和2B4）的表达、CD8 + T细胞的功能特征以及记忆分化之间的关系。在慢性感染个体中，总CD8 + T细胞上PD - 1、CD160和2B4的表达升高，且与T - bet低表达Eomes高表达的特征高度相关。有趣的是，在慢性感染中，静息和活化的HIV特异性CD8 + T细胞几乎完全是T - bet低表达Eomes高表达的细胞，而巨细胞病毒（CMV）特异性CD8 + T细胞则呈现T - bet和Eomes平衡的表达模式。T - bet低表达Eomes高表达的病毒特异性CD8 + T细胞未显示终末分化的特征，而是具有过渡性记忆表型，且多功能（效应）特性较差。HIV特异性CD8 + T细胞的过渡性和耗竭表型与抗逆转录病毒治疗（ART）启动后Eomes的持续表达呈纵向相关。令人惊讶的是，这些特征在ART启动后长达10年仍保持稳定。本研究支持这样一种观点，即人类病毒特异性CD8 + T细胞功能不良是由于T - bet和Eomes之间的反向表达失衡，尽管通过ART实现了长期的病毒控制，但这种失衡并未逆转。这些结果有助于解释为什么HIV特异性CD8 + T细胞在ART停止后无法控制病毒复制。
在接受治疗和未接受治疗的HIV感染中，CD8 + T细胞都表现出许多严重功能障碍的特征。先前的研究表明，大多数个体中的HIV特异性CD8 + T细胞具有较差的多功能性以及不成熟/偏向性成熟表型。然而，目前尚不清楚是哪些转录程序调控HIV感染中CD8 + T细胞的分化和耗竭。T - bet和Eomes是CD8 + T细胞分化和功能的两个关键转录因子，但令人惊讶的是，人们对它们在人类慢性病毒感染后对效应免疫的影响知之甚少。在本研究中，我们证明HIV特异性CD8 + T细胞具有高水平的Eomes，但T - bet表达较低。这种差异关系与几种抑制性受体的上调、病毒特异性CD8 + T细胞功能特性受损以及过渡性记忆分化表型相关。重要的是，尽管进行了多年的抑制性ART治疗，HIV特异性CD8 + T细胞的这些特征仍然保持稳定。这些结果暗示，激活这些细胞可能无法引发有效的反应来根除病毒储存库。
CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation. CD8+ T cells display numerous traits of severe dysfunction in both treated and untreated HIV infection. Previous studies have demonstrated that HIV-specific CD8+ T cells in most individuals possess poor polyfunctionality, and an immature/skewed maturation phenotype. However, it remains unclear which transcriptional programming governs the regulation of CD8+ T cell differentiation and exhaustion in HIV infection. T-bet and Eomes represent two key transcription factors for CD8+ T cell differentiation and function, but surprisingly little is known about their influence of effector immunity following chronic viral infections in humans. In this study, we demonstrate that HIV-specific CD8+ T cells possess highly elevated levels of Eomes, but low T-bet expression. This differential relationship is linked to the up-regulation of several inhibitory receptors, impaired functional characteristics and a transitional memory differentiation phenotype for virus-specific CD8+ T cells. Importantly, these characteristics of HIV-specific CD8+ T cells remained stable despite suppressive ART for many years. These results implicate that reinvigoration of these cells might fail to elicit efficient responses to eradicate the viral reservoir.
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影响因子：
4.4
作者：
Buggert, Marcus;Frederiksen, Juliet;Karlsson, Annika C.
通讯作者：
Karlsson, Annika C.
影响因子：
3.7
作者：
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通讯作者：
Karlsson AC
DOI：
10.1084/jem.20070784
发表时间：
2007-10-01
期刊：
The Journal of experimental medicine
影响因子：
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Appay V
影响因子：
20.3
作者：
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通讯作者：
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影响因子：
30.5
作者：
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通讯作者：
Reiner, SL