Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly.
Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly.
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DOI：
10.1371/journal.ppat.1009367
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Izopet J
中科院分区：
文献类型：
--
作者：
El Costa H;Gouilly J;Abravanel F;Bahraoui E;Peron JM;Kamar N;Jabrane-Ferrat N;Izopet J
基因3型戊型肝炎病毒（HEV-3）是一种新兴的威胁老龄化人口。超过三分之一的老年感染者出现临床症状并伴有严重肝损伤，而其他人则保持无症状。尽管HEV-3的发病机制似乎是免疫介导的，但这种差异的起源仍然难以捉摸。因此，我们研究了CD 8 T细胞在免疫功能正常的老年受试者感染结果中的作用。我们招募了22名表现出相似病毒决定簇的HEV-3感染患者和15名健康供体。在感染组中，16名患者出现了与肝病相关的临床症状，6名患者没有症状。在这里，我们报告说，症状性感染的特点是高度活化的效应记忆CD 8 T（EM）细胞的扩增，无论抗原特异性。这种强大的激活与早期T细胞耗竭的关键特征相关，包括多功能1型细胞因子产生的损失和部分定型为2型细胞。此外，我们发现，旁观者激活EM细胞似乎是依赖于炎症细胞因子IL-15和IL-18，并支持的上调活化受体NKG 2D和旺盛的表达T-Bet和T-Bet调节的基因，包括颗粒酶B和CXCR 3。我们还表明，炎症趋化因子CXCL 9 -10在有症状的患者中增加，从而以CXCR 3依赖的方式促进高细胞毒性EM细胞招募到肝脏中。最后，我们发现EM偏向的免疫应答在病毒清除和疾病消退后恢复稳态，进一步将EM细胞应答与病毒负荷联系起来。相反，无症状患者具有低至中度EM细胞应答。总之，我们的研究结果定义了有助于HEV-3发病机制的免疫相关性，并强调了EM细胞在控制感染结果中的核心作用。基因3型戊型肝炎病毒（HEV-3）感染的结果在老年人中存在差异。一些患者发展为严重的戊型肝炎，而另一些患者则保持无症状。尽管如此，导致严重感染与无症状感染的参数在很大程度上是未知的。因此，我们研究了感染患者（年龄≥55岁）中CD 8 T细胞的免疫学特征，这些患者具有相似的病毒决定簇但具有不同的临床结局。我们发现，剧烈的表型变化，特别是观察到效应记忆（EM）隔室。与无症状患者相比，有症状的患者显示出与细胞因子产生的定性和定量改变相关的HEV-3特异性和非特异性EM CD 8 T细胞的强烈活化。此外，EM细胞被赋予高细胞毒性能力，并具有快速迁移到肝脏的能力。最后，我们报告了对HEV-3感染的炎症反应在有症状的老年患者中形成EM细胞活化和功能。总之，我们的研究结果提出了第一份报告，证明EM CD 8 T细胞反应的性质和幅度在老年人HEV-3感染的结果中起着重要作用。
Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. The outcome of Genotype 3 Hepatitis E virus (HEV-3) infection differs among the elderly. Some patients develop severe forms of Hepatitis E while others remain asymptomatic. Nonetheless, parameters which can lead to severe versus silent infection are largely unknown. Therefore, we investigated immunological features of CD8 T cells in infected patients (aged ≥55) with similar viral determinants but distinct clinical outcomes. We show that drastic phenotypic changes were specifically observed within the effector memory (EM) compartment. Compared to asymptomatic patients, symptomatic ones display a strong activation of both HEV-3-specific and -nonspecific EM CD8 T cells associated with qualitative and quantitative alterations in cytokine production. In addition, EM cells are endowed with high cytotoxic capacity and have the ability to rapidly migrate to the liver. Finally, we report that the inflammatory response to HEV-3 infection shape EM cell activation and function in symptomatic elderly patients. In summary, our results present the first report demonstrating that the nature and the magnitude of EM CD8 T cell response play an important role in the outcome of HEV-3 infection in the elderly.
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影响因子：
15.3
作者：
Das, Abhishek;Hoare, Matthew;Davies, Nathan;Lopes, A. Ross;Dunn, Claire;Kennedy, Patrick T. F.;Alexander, Graeme;Finney, Helene;Lawson, Alistair;Plunkett, Fiona J.;Bertoletti, Antonio;Akbar, Arne N.;Maini, Mala K.
通讯作者：
Maini, Mala K.
影响因子：
12.8
作者：
Kim, Tae-Shin;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
影响因子：
4.4
作者：
Kienzle, N;Olver, S;Kelso, A
通讯作者：
Kelso, A
DOI：
10.1073/pnas.1203543109
发表时间：
2012-06-19
影响因子：
11.1
作者：
Freeman, Bailey E.;Hammarlund, Erika;Slifka, Mark K.
通讯作者：
Slifka, Mark K.
影响因子：
30.5
作者：
Carr EJ;Dooley J;Garcia-Perez JE;Lagou V;Lee JC;Wouters C;Meyts I;Goris A;Boeckxstaens G;Linterman MA;Liston A
通讯作者：
Liston A