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: 8811097
• 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/8811097
• 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; Health; 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; co-infection; design; extracellular; immunogenic; immunogenicity; in vivo; mouse model; prevent; 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会产生强烈的 CD8+ T 细胞反应。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 CD4+ T 细胞和抗体，但这些病毒几乎完全避免触发幼稚 CD8+ T 细胞。在此，我们将使用 CVB3 小鼠模型来研究肠道病毒实现这一非凡壮举的机制。当幼稚 CD8+ 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，就会启动抗病毒 CD8+ T 细胞应答。一些病毒可以感染树突状细胞，在这种情况下，内源性（即在树突状细胞内）合成的蛋白质将进入细胞的 MHC I 类途径，最终触发 CD8+ T 细胞；这个过程称为直接启动。然而，至少有两种情况不能发生直接启动。首先，一些感染 DC 的病毒还编码非常有效地抑制 MHC I 类呈递的蛋白质，使受感染的 DC 无法呈递抗原。其次，许多病毒不感染树突状细胞。尽管如此，在这两种情况下，宿主仍然对大多数病毒产生强烈的 CD8+ T 细胞反应。现在已知，从受感染细胞释放的病毒蛋白可以被未受感染的 DC 子集吸收，从而使免疫原性蛋白与 MHC 抑制蛋白分离；这些 DC 可以在 MHC I 类上呈递病毒表位。这个过程称为交叉呈递，如果它导致幼稚 CD8+ T 细胞的触发，则称为交叉引发。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 CD8+ T 细胞反应。为什么 CVB3 不能这样做？在目标 1 中，我将研究 CVB3 特异性抑制交叉引发途径、防止未感染的宿主 DC 捕获病毒蛋白的可能性。此外，我还想到了另一种解释：免疫信息可能不是以蛋白质的形式，而是以mRNA的形式传递，而肠道病毒逃避CD8+ T细胞的独特能力源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，因为它还可以解释 CD8+ T 细胞对细胞外细菌缺乏反应的原因。目标 2 和 3 测试了这个新的、可能很重要的假设。目标 1. 评估 CVB3 感染对交叉呈递/交叉引发的影响。目标 2. 询问 mRNA 编码策略是否解释了肠道病毒如何几乎完全逃避初始 CD8+ T 细胞，而大多数病毒却诱导强烈的 CD8+ T 细胞反应。目标 3. 确定 mRNA 调控序列是否可以解释为什么胞外细菌无法诱导强烈的 CD8+ T 细胞反应。