Maintenance of the virus-specific T cell equillibrium in chronic MCMV infection

描述(申请人提供)：巨细胞病毒是一种β-疱疹病毒，在世界范围内的大多数人中建立慢性/持续性感染。尽管病毒持续在极低的水平，免疫系统，特别是T细胞，变得痴迷于感染：CMV特异性CD8T细胞通常可以占感染者外周血中所有CD8T细胞的10%。来自感染小鼠巨细胞病毒(MCMV)的小鼠的数据显示，CDS T细胞在急性感染后开始积累，直到达到慢性感染期间循环中的高数量，这一过程被称为记忆膨胀。在人类和小鼠中，这些膨胀的T细胞都具有一种表型，表明存在广泛的抗原驱动分化。然而，即使在感染后的晚期，T细胞仍然具有功能和增殖能力。我们最近发现，在慢性感染期间，这些MCMV特异性T细胞群只会零星分裂，在循环中生存时间很短，并且随着它们的消失而不断被替换。因此，这些循环中的CMV特异性T细胞是高度动态的，它们以足够大的数量存在，足以扰乱整个CD8 T细胞池。我们推测，分化细胞的这种持续衰退和替换可以避免在其他慢性感染模型中看到的T细胞功能障碍。然而，最终，CMV感染与老年人T细胞的大量克隆性扩张有关，这表明最终，早期在慢性感染中建立的动态平衡被破坏。这些克隆性扩张由功能失调的T细胞组成，它们的存在与老年时的免疫风险表型有关。我们假设，这些扩张是因为一些细胞随着感染者年龄的增长而分裂而不是腐烂。了解健康成年人如何建立和维持动态平衡是很重要的，这样才能理解它是如何随着年龄的增长而丧失的。这项资助中概述的实验旨在定位和跟踪在慢性感染期间对病毒抗原做出反应并产生分化的、短暂的后代的细胞，并剖析病毒基因表达对CD8 T细胞积累的影响。

DESCRIPTION (provided by applicant): Cytomegalovirus is a beta-herpesvirus that establishes chronic/persistent infections in the majority of people world-wide. Despite the fact that the virus persists at extremely low levels, the immune system, and T cells in particular, become obsessed with the infection: CMV-specific CD8 T cells can regularly comprise 10% of all CD8 T cells in the peripheral blood of infected individuals. Data from mice infected with murine cytomegalovirus (MCMV) have shown that CDS T cells begin accumulating after acute infection until reaching the high numbers seen in circulation during chronic infection, a process known as memory inflation. In both humans and mice, these inflated T cells bear a phenotype that is indicative of extensive antigen-driven differentiation. Yet the T cells remain functional and retain proliferative potential even at late times post infection. We have recently shown that during chronic infection, these MCMV-specific T cell populations divide only sporadically, are short-lived in circulation and are being constantly replaced as they disappear. Thus, these circulating CMV-specific T cells, that exist in large enough numbers to perturb the total CD8 T cell pool, are highly dynamic. We postulate that this constant decay and replacement of differentiated cells avoids the T cell dysfunction that is seen in other models of chronic infection. Ultimately however, CMV infection is associated with large T cell clonal expansions in aged individuals, suggesting that eventually, the dynamic equilibrium that was established early in chronic infection is lost. These clonal expansions consist of dysfunctional T cells and their presence is associated with an immune risk phenotype in old age. We hypothesize that these expansions arise because some cells divide rather than decay as infected individuals get older. It is important to understand how the dynamic equilibrium is established and maintained in healthy adults in order to understand how it is lost with age. The experiments outlined in this grant are designed to locate and follow the cells that respond to viral antigen and produce differentiated, short-lived progeny during chronic infection and to dissect the impact of viral gene expression on the accumulation of CD8 T cells.