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

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CD8+ T细胞反应。然而，有一种病毒属——肠道病毒——是一个明显的例外。这些病毒可以在体内复制到非常高的滴度，它们诱导CD4+ T细胞和抗体，但这些病毒几乎完全避免触发na - CD8+ T细胞。在此，使用CVB3小鼠模型，我们将研究肠道病毒实现这一非凡壮举的机制。当na - ve CD8+ T细胞与树突状细胞（dc）表面的MHC类I /表位肽复合物接触被激活（或“启动”）时，就会启动抗病毒CD8+ T细胞反应。一些病毒可以感染DC，在这种情况下，它们的蛋白质内源性合成（即DC内）将进入细胞的MHC I类途径，最终触发CD8+ T细胞；这个过程被称为直接启动。然而，至少有两种情况不能发生直接启动。首先，一些感染DC的病毒也会编码一些蛋白质，这些蛋白质可以非常有效地抑制MHC I类呈递，使受感染的DC无法呈递抗原。其次，许多病毒不会感染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CD8+ T细胞反应。现在已经知道，从感染细胞中释放出来的病毒蛋白可以被未感染的dc亚群吸收，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，这一过程被称为交叉呈递，如果它导致初始CD8+ T细胞的触发，则称为交叉引物。这就解释了免疫系统如何对几乎所有的急性病毒感染产生强烈的CD8+ T细胞反应。为什么它不能为CVB3这样做？在Aim 1中，我将研究CVB3特异性抑制交叉引物途径的可能性，阻止未感染的宿主dc捕获病毒蛋白。此外，我还设想了另一种解释：免疫信息可能不是以蛋白质的形式传递，而是以mRNA的形式传递，肠病毒逃避CD8+ T细胞的独特能力源于这些病毒不同寻常的编码策略。这种mRNA转移的想法可能比肠病毒更重要，因为它也可以解释CD8+ T细胞对细胞外细菌反应的缺失。目标2和3测试了这个新的、潜在的重要假设。目的1。评估CVB3感染对交叉呈递/交叉启动的影响。目标2。询问mRNA编码策略是否解释了肠病毒如何几乎完全逃避幼稚CD8+ T细胞，而大多数病毒诱导强烈的CD8+ T细胞反应。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CD8+ T细胞反应。

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.