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？

基本信息

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
项目类别：
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

项目摘要

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（通过应用程序证明）：免疫系统对几乎Alduste病毒感染的强烈CD8+ T细胞反应。抗体，但这些病毒几乎完全避免触发Na¿ VE CD8+ T细胞。我们将研究肠道病毒的机制。 VE CD8+ T细胞通过与树突状细胞表面上的MHC I /表位肽复合物接触（DC）会激活（或“启动”）。在细胞I途径中，在DC中，最终触发CD8+ T细胞； E至少两种直接启动的场所，某些感染了DCS ALSSO的病毒，这些病毒非常抑制了MHC类的蛋白不感染DC，但在这两种情况下，宿主仍然对大多数病毒的响应进行了强烈的CD8+ T细胞反应。蛋白质；这些DC可以在MHC类上呈现病毒表位。该过程称为交叉呈阳性，并且对CVB3的cD8+ T细胞反应几乎是对CVB3的。 CVB3特别抑制了从捕获病毒蛋白的交叉宣传途径。不寻常的编码是肠道的范围交叉呈现 /交叉播种。 T细胞反应。