IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
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DOI：
10.1371/journal.ppat.1003362
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Kopf M
中科院分区：
文献类型：
--
作者：
Schmitz I;Schneider C;Fröhlich A;Frebel H;Christ D;Leonard WJ;Sparwasser T;Oxenius A;Freigang S;Kopf M
Foxp3+ 调节性 T (Treg) 细胞对于维持免疫稳态和耐受性至关重要。在病毒感染期间，Treg 细胞可以限制过度炎症引起的免疫病理学，但有可能抑制有效的抗病毒 T 细胞反应并促进病毒持续存在。我们在这里报告，快速复制的 LCMV 毒株 Docile 引发了 Treg 群体的大规模扩张，这与病毒接种量及其建立慢性持续感染的趋势直接相关。这种 Treg 细胞增殖在 IL-21R−/− 小鼠中大大增强，Treg 细胞的耗竭部分挽救了有缺陷的 CD8+ T 细胞细胞因子反应，并改善了一些但不是所有器官的病毒清除率。值得注意的是，IL-21 以细胞固有的方式抑制 Treg 细胞的扩增。此外，通过注射IL-2/抗IL-2免疫复合物驱动的Treg细胞的实验性增强极大地损害了抗病毒T细胞反应的功能并阻碍了病毒清除。因此，小鼠在接触低剂量病毒后变得非常容易受到慢性感染。这些发现揭示了病毒驱动的 Treg 细胞增殖是潜在的逃避策略，可促进 T 细胞耗竭和病毒持续存在。此外，他们认为，除了在慢性感染期间作为抗病毒 CD8+ T 细胞的直接生存信号的主要功能外，IL-21 还可能通过限制感染诱导的 Treg 细胞的抑制活性来间接促进 CD8+ T 细胞的多功能性。 T 细胞耗竭代表与临床相关疾病（例如持续性病毒感染或癌症）相关的 T 细胞功能障碍状态。尽管已在功能和转录水平上详细描述了耗竭 T 细胞的分子特征，但慢性感染期间导致 T 细胞耗竭的免疫机制仍知之甚少。我们目前的研究报告了两项主要发现，说明了病毒感染期间导致 T 细胞耗竭的途径，并表明了病原体和宿主对 T 细胞的调节。首先，我们证明持久性诱导病毒会触发 Foxp3+ 调节性 T (Treg) 细胞的大量增殖，并证明 Treg 细胞促进 T 细胞耗竭和慢性感染的潜力。其次，我们将 IL-21 确定为一个关键的宿主因子，它以独立于 IL-2 的细胞内在方式拮抗这种病毒驱动的 Treg 群体的扩张。因此，除了已知的对抗病毒 T 细胞具有显着的直接积极作用外，IL-21 还可以减轻 Treg 细胞的抑制活性。总之，这些结果表明增强的 Treg 细胞反应是一种免疫逃避机制，可以通过 IL-21 进行治疗。
Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R−/− mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells. T cell exhaustion represents a state of T cell dysfunction associated with clinically relevant diseases, such as persistent viral infections or cancer. Although the molecular signature of exhausted T cells has been characterized in detail at the functional and transcriptional level, the immunological mechanisms that lead to T cell exhaustion during chronic infections remain poorly understood. Our present study reports two major findings that illustrate a pathway that contributes to T cell exhaustion during viral infection, and indicate its modulation by both, the pathogen and the host. First, we show that a persistence-inducing virus triggers the massive proliferation of Foxp3+ regulatory T (Treg) cells and demonstrate the potential of Treg cells to promote T cell exhaustion and chronic infection. Second, we identify IL-21 as a crucial host factor that antagonizes this virus-driven expansion of the Treg population in a cell intrinsic manner independent of IL-2. Thus, in addition to its known pre-dominant direct positive effects on antiviral T cells, IL-21 can also alleviate the suppressive activity of Treg cells. Together, these results suggest enhanced Treg cell responses as a mechanism of immune evasion that could be therapeutically targeted with IL-21.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.4049/jimmunol.1000423
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fulton RB;Meyerholz DK;Varga SM
通讯作者：
Varga SM
DOI：
10.1073/pnas.1015148108
发表时间：
2011-02-08
影响因子：
11.1
作者：
Dietze, Kirsten K.;Zelinskyy, Gennadiy;Dittmer, Ulf
通讯作者：
Dittmer, Ulf
影响因子：
56.9
作者：
Altman, JD;Moss, PAH;Davis, MM
通讯作者：
Davis, MM