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

描述（由申请人提供）：巨细胞病毒是一种乙型疱疹病毒，在全世界大多数人中建立慢性/持续性感染。尽管这种病毒持续处于极低水平，但免疫系统，尤其是T细胞，对这种感染变得痴迷：cmv特异性CD8 T细胞通常占感染者外周血中所有CD8 T细胞的10%。来自感染小鼠巨细胞病毒（MCMV）的小鼠的数据表明，CDS T细胞在急性感染后开始积累，直到达到慢性感染时循环中所见的高数量，这一过程被称为记忆膨胀。在人类和小鼠中，这些膨胀的T细胞具有一种表型，表明广泛的抗原驱动分化。然而，即使在感染后的后期，T细胞仍保持功能和增殖潜力。我们最近表明，在慢性感染期间，这些mcmv特异性T细胞群只是偶尔分裂，在循环中是短暂的，并且随着它们的消失而不断被替换。因此，这些循环的cmv特异性T细胞数量足够大，足以扰乱整个CD8 T细胞库，它们是高度动态的。我们假设这种分化细胞的持续衰变和替换避免了在其他慢性感染模型中看到的T细胞功能障碍。然而，CMV感染最终与老年个体的大T细胞克隆扩增有关，这表明在慢性感染早期建立的动态平衡最终会丢失。这些克隆扩增由功能失调的T细胞组成，它们的存在与老年免疫风险表型相关。我们假设，这些扩张的出现是因为随着受感染个体变老，一些细胞会分裂而不是腐烂。了解动态平衡是如何在健康成人中建立和维持的，以便了解它是如何随着年龄的增长而丧失的，这一点很重要。本基金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作出反应并产生分化的短期后代的细胞，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.