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（由适用提供）：免疫系统对几乎所有急性病毒感染的CD8+ T细胞反应都具有强大的CD8+ T细胞反应。但是，一个病毒属 - 肠病毒 - 是一个鲜明的例外。这些病毒可以在体内复制至极高的滴度，并影响CD4+ T细胞和抗体，但是这些病毒几乎完全避免触发Na¿veCD8+ T细胞。在此，使用CVB3鼠标模型，我们将研究肠病毒实现这一非凡壮举的机制。当Na¿veVE CD8+ T细胞通过与树突状细胞表面（DCS）表面上的MHC I /表位肽复合物接触而激活（或“启动”）时，抗病毒CD8+ T细胞反应会开始。某些病毒可以感染DC，在这种情况下，内生（即在DC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。此过程称为直接启动。但是，至少有两种情况无法进行直接启动。首先，某些感染DC的病毒还编码非常有效抑制I类表现的蛋白质，从而使被感染的DC无法抗原呈递。其次，许多病毒未感染DC。然而，在这两种情况下，宿主仍然对大多数病毒的CD8+ T细胞反应均具有强大的态度。现在已经知道，已经从感染细胞中释放的病毒蛋白可以通过未感染的DC的一部分来吸收，从而使免疫原性蛋白与MHC抑制蛋白分离。这些DC可以在MHC类I上呈现病毒表位。此过程称为交叉呈递，如果它导致启发幼稚的CD8+ T细胞，则称为交叉播种。这解释了免疫系统如何对几乎所有急性病毒感染的强烈CD8+ T细胞反应施加强烈的反应。 CVB3为什么不能这样做？在AIM 1中，我将研究CVB3专门抑制交叉式途径的可能性，以防止未感染的宿主DC捕获病毒蛋白。此外，我想到了另一种解释：免疫信息可能不是作为蛋白质转移的，而是作为mRNA传递，并且肠病毒逃避CD8+ T细胞的独特能力是由这些病毒的异常编码策略产生的。这种mRNA转移想法在肠病毒之外可能很重要，因为它也可以解释CD8+ T细胞对细胞外细菌的反应的不存在。目标2和3测试了这个新的，可能重要的假设。目的1。评估CVB3感染对交叉呈现 /交叉染色的影响。目的2。询问mRNA编码策略是否解释了肠病毒如何几乎可以完全逃避幼稚的CD8+ T细胞，而大多数病毒会诱导强大的CD8+ T细胞反应。目的3。确定mRNA调节序列是否解释了为什么细胞外细菌无法诱导强大的CD8+ T细胞反应。