miRNA-mediated premature T cell aging in vaccine failure during viral infection

描述（由申请人提供）：本提案的总体目标是阐明慢性感染通过调节microrna介导T细胞过早衰老并导致疫苗反应减弱的机制，目的是开发有效的方法来提高病毒感染个体的疫苗效力。为此，我们将在慢性丙型肝炎病毒（HCV）感染的情况下使用乙型肝炎病毒（HBV）疫苗失败模型。该建议是基于这样一个事实，即由于共同的危险因素，HBV与HCV和/或HIV合并感染是常见的，因此需要HBV疫苗来预防重复感染及其相关的发病率和死亡率增加；然而，病毒感染个体的疫苗反应往往是迟钝的。这一现象在老年人中也存在，他们经常对疫苗接种没有反应，而且在受感染人口和老年人口中提高免疫率的努力也没有成功。这在一定程度上是由于我们对这些情况下抑制疫苗反应的机制了解不足。在研究病毒感染对T细胞功能的影响时，我们和其他研究人员最近发现慢性HCV感染通过上调衰老标志物介导T细胞功能障碍，包括杀伤细胞凝集素样受体亚家族G成员1 （KLRG1）和双特异性磷酸酶6 (DUSP6)，并伴有CD4 T细胞中microRNA-181a （miR181）水平的下降。值得注意的是，这些改变与hcv感染个体的CD4 T细胞功能受损有关，并且与年龄匹配的HBV疫苗应答者（HBV- r）相比，在HBV疫苗无应答者（HBV- nr）中更为突出。随着年龄的增长，KLRG1上调，导致T细胞受体（TCR）信号的抑制，而DUSP6上调，导致TCR激活阈值的重新校准；miR181不允许翻译一组与T细胞抑制相关的基因。然而，HCV感染期间miR181/KLRG1/DUSP6表达和调控T细胞过早衰老和疫苗应答的机制尚不清楚。在本研究中，我们假设hcv诱导的miR181缺失通过上调KLRG1和/或DUSP6表达介导T细胞过早衰老，因此靶向这些抑制途径可能挽救受损的CD4 T细胞功能，并随后增强病毒感染个体的钝疫苗反应。为了验证这一假设，我们将进行以下三个具体目标：目标1将定义

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the mechanisms by which chronic infection mediates premature T cell aging through regulation of microRNAs and leading to blunted vaccine responses, with an aim to develop effective approaches to improve vaccine efficacy in virus-infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine failure in the setting of chronic hepatitis C virus (HCV) infection. The proposal is based on the fact that co-infection of HBV with HCV and/or HIV is common due to shared risk factors, and as such HBV vaccine is required to prevent super-infection and its associated increase in morbidity and mortality; however, vaccine responses in virus-infected individuals are often blunted. This phenomenon is also observed in the elderly, who frequently fail to respond to vaccinations and attempts to improve the rate of immunizations in both infected and aged populations have been unsuccessful. This is in part due to our poor understanding of the mechanisms that inhibit vaccine responses in these settings. In studying the effect of viral infection on T cell functions, we and others have recently found that chronic HCV infection leads to T cell dysfunction mediated through up-regulation of aging markers, including killer cell lectin- like receptor subfamily G member 1 (KLRG1) and dual specific phosphatase 6 (DUSP6), concomitant with a decline of microRNA-181a (miR181) levels in CD4 T cells. Remarkably, these alterations are associated with impaired CD4 T cell functions in HCV-infected individuals and are more prominent in HBV vaccine non- responders (HBV-NR) compared to age-matched HBV vaccine responders (HBV-R). With increasing age, KLRG1 is up-regulated and leads to inhibition of T cell receptor (TCR) signaling, whereas DUSP6 is increased and leads to recalibration of the TCR activation threshold; miR181 declines to permit translation of a set of genes related to T cell inhibition. However, the mechanisms underlying miR181/KLRG1/DUSP6 expression and regulation of premature T cell aging and vaccine responses during HCV infection remain unknown. In this proposal, we hypothesize that HCV-induced loss of miR181 mediates premature T cell aging by up-regulating KLRG1 and/or DUSP6 expressions, such that targeting these inhibitory pathways may rescue impaired CD4 T cell functions and subsequently boost blunted vaccine responses in virus-infected individuals. To test this hypothesis, we will carry out the following three specific aims: Aim 1 will define the epigenetic, transcriptional and translational mechanisms that control miR181 expression in T cells during HCV infection; Aim 2 will determine the role of miR181 in regulating KLRG1 and/or DUSP6 expression in T cells during HCV infection; Aim 3 will examine the consequences of miR181 loss and KLRG1/DUSP6 expression in T cell function and vaccine response in virus-infected individuals. This translational study is significant in that it provides a working model t explore mechanisms that may be fundamental to diminished vaccine responses in general, particularly in the setting of immunocompromise by HIV, hemodialysis, transplantation, and cancer.