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

描述(申请人提供)：免疫系统对几乎所有的急性病毒感染都有很强的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极高的滴度，它们可以诱导CD4+T细胞和抗体，但这些病毒几乎完全避免触发天然的CD8+T细胞。在这里，我们将利用CVB3小鼠模型，研究肠道病毒实现这一非凡壮举的机制(S)。当CD8+T细胞通过与树突状细胞(DC)表面的MHC I类/表位多肽复合体接触而被激活(或“启动”)时，抗病毒CD8+T细胞应答被启动。一些病毒可以感染树突状细胞，在这种情况下，内源性合成的蛋白质(即在树突状细胞内)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的病毒还编码非常有效地抑制MHC I类递呈的蛋白质，使受感染的DC不能递呈抗原。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有很强的CD8+T细胞反应。现在已经知道，从感染细胞中释放的病毒蛋白可以被未感染的树突状细胞的子集所摄取，从而使免疫原性蛋白从MHC抑制蛋白中分离出来；这些树突状细胞可以呈现MHC I类分子上的病毒表位。这个过程被称为交叉提呈，如果它导致初始CD8+T细胞的触发，则称为交叉激发。这解释了免疫系统如何对几乎所有的急性病毒感染产生强大的CD8+T细胞反应。为什么它不能对CVB3这样做呢？在目标1中，我将研究CVB3特异性地抑制交叉启动途径的可能性，防止未受感染的宿主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。这种信使核糖核酸转移的想法可能比肠道病毒更重要，因为它也可以解释CD8+T细胞对胞外细菌没有反应。目标2和目标3验证了这一新的、潜在重要的假设。目的1.探讨CVB3感染对交叉呈现/交叉启动的影响。目的2.探讨mRNA编码策略是否能解释肠道病毒如何几乎完全逃避初始的CD8+T细胞，而大多数病毒诱导强烈的CD8+T细胞反应。目的3.确定信使核糖核酸调控序列是否能解释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.