How do enteroviruses almost completely evade the attentions of CD8+ T cells?

肠道病毒是如何几乎完全逃避CD8 T细胞的注意的？

• 批准号: 8630094
• 负责人: J. Lindsay Whitton
• 金额: $ 41.47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630094
• 关键词: Acute; Affect; Antibodies; Antigen Presentation; Antiviral Agents; Attention; Bacteria; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Code; Complex; Coxsackie Viruses; Cross Presentation; Cross-Priming; DNA Viruses; Data; Dendritic Cells; Educational process of instructing; Enterovirus; Epitopes; Eukaryotic Cell; Family; Immune; Immune system; In Vitro; Infection; Link; MHC Class I Genes; Memory; Messenger RNA; Mus; Pathway interactions; Peptides; Phenotype; Process; Proteins; RNA Viruses; Route; Surface; T cell response; T-Lymphocyte; Testing; Translating; Viral; Viral Proteins; Virus; Virus Diseases; Work; cell type; design; extracellular; immunogenic; immunogenicity; in vivo; mouse model; prevent; public health relevance; research study; uptake

DESCRIPTION (provided by applicant): The immune system mounts strong CD8+ T cell responses to almost all acute virus infections. However, one virus genus - the enteroviruses - is a stark exception. These viruses can replicate to extremely high titers in vivo, and they induce CD4+ T cells and antibodies, yet these viruses almost completely avoid triggering na¿ve CD8+ T cells. Herein, using the CVB3 mouse model, we shall investigate the mechanism(s) by which enteroviruses achieve this remarkable feat. Antiviral CD8+ T cell responses are initiated when na¿ve CD8+ T cells are activated (or "primed") by contact with an MHC class I / epitope peptide complex on the surface of dendritic cells (DCs). Some viruses can infect DCs, in which case their proteins, being synthesized endogenously (i.e., within the DC) will enter the cell's MHC class I pathway, ultimately triggering CD8+ T cells; this process is called direct priming. However, there are at least two situations in which direct priming cannot occur. First, some viruses that infect DCs also encode proteins that very effectively inhibit MHC class I presentation, rendering the infected DC incapable of antigen presentation. Second, many viruses do not infect DCs. Nevertheless, in both of these cases, the host still mounts strong CD8+ T cell responses to most viruses. It is now known that viral proteins that have been released from infected cells can be taken up by a subset of uninfected DCs, allowing immunogenic proteins to be separated from MHC-inhibitory proteins; these DCs can present viral epitopes on MHC class I. This process is called cross-presentation and, if it results in the triggering of naive CD8+ T cells, it is termed cross-priming. This explains how the immune system can mount strong CD8+ T cell responses to almost all acute virus infections. Why can't it do so for CVB3? In Aim 1, I will investigate the possibility that CVB3 specifically inhibits the cross-priming pathway, preventing uninfected host DCs from capturing viral proteins. In addition, I have conceived of another explanation: that immunological information may be transferred not as protein, but as mRNA, and that the unique capacity of enteroviruses to evade CD8+ T cells results from the unusual coding strategy of these viruses. This mRNA transfer idea may be important beyond enteroviruses, because it also can explain the absence of CD8+ T cell responses to extracellular bacteria. Aims 2 & 3 test this new, and potentially-important, hypothesis. Aim 1. To assess the effect of CVB3 infection on cross-presentation / cross-priming. Aim 2. To ask if mRNA coding strategy explains how enteroviruses can almost completely evade naive CD8+ T cells, while most viruses induce strong CD8+ T cell responses. Aim 3. To determine if mRNA regulatory sequences explain why extracellular bacteria fail to induce strong CD8+ T cell responses.

描述（由申请人提供）：免疫系统对几乎所有急性病毒感染都产生强烈的CD 8 + T细胞应答。然而，一种病毒属-肠道病毒-是一个明显的例外。这些病毒可以在体内复制到极高的滴度，并诱导CD 4 + T细胞和抗体，但这些病毒几乎完全避免触发幼稚的CD 8 + T细胞。在此，我们将使用CVB 3小鼠模型研究肠道病毒实现这一显著壮举的机制。抗病毒CD 8 + T细胞应答是当幼稚CD 8 + T细胞通过与树突状细胞（DC）表面上的MHC I类/表位肽复合物接触而被激活（或“引发”）时启动的。一些病毒可以感染DC，在这种情况下，它们的蛋白质是内源性合成的（即，DC内的CD 8 + T细胞（DC内的CD 8 + T细胞）将进入细胞的MHC I类途径，最终触发CD 8 + T细胞;这一过程称为直接引发。然而，至少有两种情况不能发生直接启动。首先，一些感染DC的病毒也编码非常有效地抑制MHC I类呈递的蛋白质，使感染的DC不能呈递抗原。其次，许多病毒不感染DC。然而，在这两种情况下，宿主仍然对大多数病毒产生强烈的CD 8 + T细胞应答。目前已知，从感染细胞释放的病毒蛋白可以被未感染的DC亚群摄取，从而使免疫原性蛋白与MHC抑制蛋白分离;这些DC可以呈递I类MHC上的病毒表位。这个过程被称为交叉呈递，如果它导致初始CD 8 + T细胞的触发，它被称为交叉致敏。这解释了免疫系统如何对几乎所有急性病毒感染产生强烈的CD 8 + T细胞反应。为甚么CVB 3不可以呢？在目标1中，我将研究CVB 3特异性抑制交叉致敏通路，阻止未感染的宿主DC捕获病毒蛋白的可能性。此外，我还设想了另一种解释：免疫学信息可能不是以蛋白质的形式，而是以mRNA的形式传递，肠道病毒逃避CD 8 + T细胞的独特能力来自于这些病毒不寻常的编码策略。这种mRNA转移的想法可能比肠道病毒更重要，因为它也可以解释CD 8 + T细胞对细胞外细菌反应的缺乏。目标2和3测试这个新的，潜在的重要假设。目标1.评估CVB 3感染对交叉呈递/交叉致敏的影响。目标二。为了询问mRNA编码策略是否解释了肠道病毒如何几乎完全逃避幼稚CD 8 + T细胞，而大多数病毒诱导强烈的CD 8 + T细胞应答。目标3.确定mRNA调控序列是否解释了为什么胞外细菌不能诱导强烈的CD 8 + T细胞应答。