Tissue-specific control of latent CMV reactivation by regulatory T cells.
Tissue-specific control of latent CMV reactivation by regulatory T cells.
复制标题
DOI：
10.1371/journal.ppat.1006507
复制
发表时间：
2017-08
期刊：
影响因子：
6.7
通讯作者：
Hildeman DA
中科院分区：
文献类型：
--
作者：
Almanan M;Raynor J;Sholl A;Wang M;Chougnet C;Cardin RD;Hildeman DA
巨细胞病毒（CMV）引起持续性终身感染。CMV持续处于潜伏状态，并经历间歇性亚临床病毒再活化，其被正在进行的T细胞应答平息。虽然T细胞对维持感染控制至关重要，但促进CMV持续存在的免疫因素仍不清楚。在这里，我们研究了调节性T细胞（Treg）在潜伏性CMV感染的小鼠模型中使用Foxp 3-白喉毒素受体（Foxp 3-DTR）小鼠的作用。感染后8个月，MCMV在脾脏、唾液腺、肺和胰腺中建立了潜伏期，并伴有Treg频率增加。在建立潜伏期后给予白喉毒素（DT）有效地耗尽了Treg，并促使功能性MCMV特异性CD 4+和CD 8 + T细胞的数量显著增加。引人注目的是，Treg耗竭减少了脾脏中具有可再活化潜伏MCMV的动物数量。出乎意料的是，在相同的动物中，Treg的消融驱动了唾液腺中病毒再活化的显著增加，伴随着Foxp 3-CD 4 +T细胞的局部IL-10产生的增加。此外，Treg耗竭后IL-10的中和显著降低了唾液腺中的病毒载量。结合起来，这些数据显示Treg根据组织对MCMV感染具有不同的控制。在脾脏中，Treg拮抗CD 8+效应子功能并促进病毒持续存在，而在唾液腺中，Treg阻止IL-10产生并限制病毒再活化和复制。这些数据为Treg在控制潜伏MCMV感染再激活中的器官特异性作用提供了新的见解。巨细胞病毒（CMV）感染在小鼠和人类中通常最初由强烈的适应性免疫反应控制，该免疫反应驱使病毒在多个组织中潜伏。然而，控制潜伏期的免疫学机制还不清楚。在这份报告中，我们研究了调节性T细胞（Treg）在CMV感染小鼠模型中的作用。有趣的是，调节性T细胞的耗竭对MCMV潜伏感染有深远的影响，这取决于组织。在脾脏中，Treg耗竭增强了CD 8 + T细胞应答并减少了来自脾脏的可再活化潜伏感染。与此形成鲜明对比的是，在唾液腺中，Treg耗竭增强了从CD 4 + T细胞产生IL-10以及病毒再活化。因此，Treg在控制MCMV从潜伏期再激活中发挥不同的和组织特异性的作用。
Cytomegalovirus (CMV) causes a persistent, lifelong infection. CMV persists in a latent state and undergoes intermittent subclinical viral reactivation that is quelled by ongoing T cell responses. While T cells are critical to maintain control of infection, the immunological factors that promote CMV persistence remain unclear. Here, we investigated the role of regulatory T cells (Treg) in a mouse model of latent CMV infection using Foxp3-diphtheria toxin receptor (Foxp3-DTR) mice. Eight months after infection, MCMV had established latency in the spleen, salivary gland, lung, and pancreas, which was accompanied by an increased frequency of Treg. Administration of diphtheria toxin (DT) after establishment of latency efficiently depleted Treg and drove a significant increase in the numbers of functional MCMV-specific CD4+ and CD8+ T cells. Strikingly, Treg depletion decreased the number of animals with reactivatable latent MCMV in the spleen. Unexpectedly, in the same animals, ablation of Treg drove a significant increase in viral reactivation in the salivary gland that was accompanied with augmented local IL-10 production by Foxp3-CD4+T cells. Further, neutralization of IL-10 after Treg depletion significantly decreased viral load in the salivary gland. Combined, these data show that Treg have divergent control of MCMV infection depending upon the tissue. In the spleen, Treg antagonize CD8+ effector function and promote viral persistence while in the salivary gland Treg prevent IL-10 production and limit viral reactivation and replication. These data provide new insights into the organ-specific roles of Treg in controlling the reactivation of latent MCMV infection. Cytomegalovirus (CMV) infection in both mice and humans is normally initially contained by a vigorous adaptive immune response that drives the virus into latency in multiple tissues. However, the immunologic mechanisms that control latency are not well understood. In this report, we have examined the role of regulatory T cells (Treg) in a mouse model of CMV infection. Interestingly, depletion of regulatory T cells had profound consequences on MCMV latent infection, depending upon the tissue. In the spleen, Treg depletion enhanced CD8+ T cell responses and reduced reactivatable latent infection from the spleen. In striking contrast, in the salivary gland, Treg depletion enhanced the production of IL-10 from CD4+ T cells as well as viral reactivation. Thus, Treg play divergent and tissue specific roles in controlling MCMV reactivation from latency.
登录
查看更多内容
巨细胞病毒利用了唾液腺中IL-10介导的免疫调节。
影响因子：
15.3
作者：
Humphreys, Ian R;de Trez, Carl;Kinkade, April;Benedict, Chris A;Croft, Michael;Ware, Carl F
通讯作者：
Ware, Carl F
影响因子：
6.7
作者：
Dietze KK;Zelinskyy G;Liu J;Kretzmer F;Schimmer S;Dittmer U
通讯作者：
Dittmer U
DOI：
10.1073/pnas.95.7.3937
发表时间：
1998-03-31
影响因子：
11.1
作者：
Hahn, G;Jores, R;Mocarski, ES
通讯作者：
Mocarski, ES
影响因子：
5.4
作者：
Grzimek, NKA;Dreis, D;Reddehase, MJ
通讯作者：
Reddehase, MJ
影响因子：
6.7
作者：
Clement, Mathew;Marsden, Morgan;Humphreys, Ian R.
通讯作者：
Humphreys, Ian R.