Immunodominance in the Human T-cell Responses to Poxvirus and Herpesvirus

细胞反应被激发到免疫反应的一些但不是所有可能的目标，并且规则是 对于表位的选择，目前还不完全清楚。这项拨款申请的主要目的是首先 研究人类T细胞对病原体反应中的表位选择；第二，研究 影响表位选择的病原体机制。将使用牛痘病毒和人类疱疹病毒6 作为模型病原体。这些都是具有许多潜在表位的大基因组DMA病毒，这些问题 表位选择和免疫层级的关系尤其密切。该提案有三个具体目标。 目的1是确定控制人类CD4+T细胞反应表位选择的因素 以痘苗病毒为模型。将评估影响表位选择的几个潜在因素，包括 多肽-MHC解离动力学、抗原在感染细胞和/或病毒中的表达水平和位置 颗粒，以及抗原是使用传统的内噬处理还是自噬处理 小路。目的2研究人类CD4+和CD8+T细胞对HHV-6病毒的应答。HHV-6是一种 相对最近发现的贝塔疱疹病毒，它建立了一种长期的潜伏感染，大多数 人是儿童时期接触的结果，是携带者。在以下情况下，病毒会重新激活 免疫抑制条件，如移植后治疗或艾滋病。尽管核心角色是 细胞免疫在控制这种病毒方面，人们对T细胞的反应知之甚少。在针对以下目标的工作中 目的2，我们将表征T细胞对HHV-6的应答，研究其特异性，并确定是否有相关因素 痘苗病毒表位选择的重要性也适用于HHV-6。许多病毒都有机制 逃避或调节对它们的免疫反应。目标3是描述抗原的调节。 在痘苗感染细胞中的加工和递送途径，并确定HHV-6是否也有 改变感染细胞中抗原处理途径的机制。

cell responses are elicited to some but not all possible targets of the immune response, and the rules that govern epitope selection are not completely clear. The main goals of this grant application are first to investigate epitope selection in the human T cell response to pathogens and second to investigate mechanisms of pathogens that affect epitope selection. Vaccinia virus and human herpesvirus 6 will be used as model pathogens. These are large-genome DMA viruses with many potential epitopes for which questions of epitope selection and immune hierarchy are particularly relevant. The proposal has three specific aims. Aim 1 is to determine factors that control epitope selection of the human CD4+ T cell response by using vaccinia virus as a model. Several potential factors affecting epitope selection will be evaluated, including peptide-MHC dissociation kinetics, antigen expression level and location in the infected cell and/or viral particle, and whether the antigen is processed using conventional endosomal processing or autophagy pathways. Aim 2 is to characterize the human CD4+ and CD8+ T cell response to HHV-6 virus. HHV-6 is a relatively recently discovered beta herpesvirus that establishes a long-lasting latent infection, and most people are carriers as a results of childhood exposure. Viral reactivation can occur under immunosuppressive conditions such a post-transplantation therapy or AIDS. Despite the central role of cellular immunity in controlling this virus, very little is known about the T cell response. In work directed at Aim 2, we will characterized the T cell response to HHV-6, study its specificity, and determine if factors important in epitope selection in vaccinia virus also apply to HHV-6. Many viruses have mechanisms to evade or modulate the immune response against them. AIM 3 is to characterize modulation of antigen processing and presentation pathways in vaccinia-infected cells, and to determine whether HHV-6 also has mechanisms to alter antigen processing pathways in infected cells.