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

细胞应答是针对免疫应答的一些但不是所有可能的靶标而引起的， 控制表位选择的因素还不完全清楚。这项拨款申请的主要目标是首先 研究人类T细胞对病原体应答中的表位选择，其次研究 病原体影响表位选择的机制。将使用牛痘病毒和人类疱疹病毒6 作为模式病原体。这些是大基因组DNA病毒，具有许多潜在的表位， 表位选择和免疫层次是特别相关的。该提案有三个具体目标。 目的1是确定控制人CD 4 + T细胞应答表位选择的因素， 牛痘病毒作为模型。将评估影响表位选择的几个潜在因素，包括 肽-MHC解离动力学、抗原表达水平和在感染细胞和/或病毒中的位置 颗粒，以及抗原是否使用常规内体加工或自噬进行加工 途径。目的二是研究人CD 4+和CD 8 + T细胞对HHV-6病毒的免疫应答。HHV-6是一种 相对最近发现的β疱疹病毒，建立一个长期的潜伏感染， 人是由于童年接触的带菌者。病毒再激活可发生在 免疫抑制状况，如移植后治疗或AIDS。尽管中心作用， 细胞免疫在控制这种病毒，很少有人知道T细胞反应。在工作中， 目的2：研究HHV-6诱导的T细胞免疫反应的特点，研究其特异性，并确定影响HHV-6诱导的T细胞免疫反应的因素 在牛痘病毒表位选择中重要性也适用于HHV-6。许多病毒都有 逃避或调节针对它们的免疫反应。目的3是表征抗原的调节 加工和呈递途径，并确定HHV-6是否也具有 改变感染细胞中抗原加工途径的机制。

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.