The CD8 T cell response to murine cytomegalovirus

巨细胞病毒(CMV)是一种物种特有的β疱疹病毒，可在 大多数哺乳动物。这种终生居住会在体内激发非常大的CD8和CD4T细胞反应 大多数宿主，具有特征的“效应记忆”(TEM)表型，并倾向于增加 数量随年龄增长，有时主宰整个老年人的CDST细胞隔间。两个悖论 这是这一标志性回应的基础。首先，大多数CDST细胞识别感染的能力很差 细胞，由于巨细胞病毒基因的功能，干扰抗原提呈。这些T细胞是如何 准备好了吗？其次，尽管在受感染的宿主中存在潜伏病毒，但几乎没有证据表明病毒活性。 驱动这种反应的抗原从何而来？这些问题将使用 C57BL/6小鼠巨细胞病毒感染模型。这项提议的第一个具体目标是检验以下假设 交叉呈现负责启动大多数CDST细胞反应。为了实现这一目标，一个 正在组装一套独特的工具：25个CMV表位之间的免疫优势等级 对C57BL/6小鼠CDS识别的T细胞进行检测。缺乏这两种能力的变异病毒 损害抗原提呈和树突状细胞上共刺激分子表达的能力 细胞正在生成，并将使用交叉呈现受损的小鼠模型。有一个 在急性和慢性感染之间识别的主要抗原的显著变化。第二个目标 解决了这种转变的原因。免疫系统在不同细胞中影响病毒活性的能力 类型，特别是内皮细胞，将被视为这种改变的免疫显性的主要原因。 最后，自相矛盾的是，庞大的、膨胀的T细胞反应是由低于 将解决检测阈值问题。CDST细胞的透射电子显微镜表型将被评估。是 这些细胞相当于急性感染消退后观察到的暂时性透射电子显微镜群体， 是因为不断地用抗原重新刺激而产生的？或者它们代表了一个静止的、长寿的人口， 就像对具有相似表型的人的透射电子显微镜所建议的那样？

Cytomegaloviruses (CMVs) are species specific beta herpesviruses that establish life long infection in the majority of mammals. This lifelong residence is provokes very large CD8 and CD4 T cell responses in the majority of hosts, that have a characteristic "effector memory" (TEM) phenotype and tend to increase in numbers with age, sometimes dominating the entire CDST cell compartment in the elderly. Two paradoxes underlie this signature response. First, the majority of CDST cells have a poor ability to recognize infected cells, due to the function of CMVs genes that interfere with antigen presentation. How are these T cells primed? Second, although latent virus is present in infected hosts, there is little evidence of virus activity. Where does the antigen come from that drives the response? These questions will be addressed using the C57BL/6 mouse model of CMV infection. The first specific aim of this proposal is to test the hypothesis that cross-presentation is responsible for priming that majority of the CDST cell response. To address this aim, a unique set of tools is being assembled: the immunodominance hierarchy amongst 25 CMV epitopes recognized by CDS T cells from C57BL/6 mice will be measured. Mutant viruses lacking both the ability to impair antigen presentation and the ability to impair the expression of co-stimulatory molecules on dendritic cells are being generated, and a mouse model of impaired cross presentation will be used. There is a marked alteration in the main antigens recognized between acute and chronic infection. The second aim addresses the cause of that shift. The ability of the immune system to impact viral activity in different cell types, particularly endothelial cells, will be addressed as a primary cause of this altered immunodominant. Finally, the paradox that the large, inflating T cell response is maintained by viral activity that is below the threshold of detection will be addressed. The TEM phenotype of the CDST cells will be evaluated. Are these cells equivalent to the transitory TEM population observed following resolution of acute infection, resulting from constant restimulation with antigen? Or do they represent a quiescent, long-lived population, as has been proposed for human TEM of a similar phenotype?