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

慢性 MCMV 感染中病毒特异性 T 细胞平衡的维持

基本信息

批准号：
8135989
负责人：
Christopher M Snyder
金额：
$ 10.8万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请方提供）：巨细胞病毒是一种β-疱疹病毒，可在全球大多数人群中造成慢性/持续性感染。尽管病毒持续存在于极低的水平，免疫系统，特别是T细胞，变得痴迷于感染：CMV特异性CD 8 T细胞通常占感染个体外周血中所有CD 8 T细胞的10%。来自感染鼠巨细胞病毒（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在循环中看到的高数量，这一过程称为记忆膨胀。在人类和小鼠中，这些膨胀的T细胞具有指示广泛抗原驱动分化的表型。然而，即使在感染后的晚期，T细胞仍保持功能性并保留增殖潜力。我们最近表明，在慢性感染期间，这些MCMV特异性T细胞群仅零星分裂，在循环中寿命很短，并且随着它们的消失而不断被替换。因此，这些以足够大的数量存在以扰乱总CD 8 T细胞库的循环CMV特异性T细胞是高度动态的。我们假设这种分化细胞的不断衰减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，最终，CMV感染与老年个体中的大T细胞克隆扩增相关，这表明最终，在慢性感染早期建立的动态平衡丢失。这些克隆扩增由功能失调的T细胞组成，它们的存在与老年人的免疫风险表型相关。我们假设这些扩张的出现是因为随着感染者变老，一些细胞分裂而不是衰变。重要的是要了解如何建立和维持健康成年人的动态平衡，以了解它是如何随着年龄的增长而失去的。本研究中概述的实验旨在定位和跟踪对病毒抗原有反应的细胞，并在慢性感染期间产生分化的短命后代，并剖析病毒基因表达对CD 8 T细胞积累的影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stochastic Expansions Maintain the Clonal Stability of CD8+ T Cell Populations Undergoing Memory Inflation Driven by Murine Cytomegalovirus.

随机扩增维持经历鼠巨细胞病毒驱动的记忆膨胀的 CD8 T 细胞群的克隆稳定性。

DOI：
10.4049/jimmunol.1900455
发表时间：
2020
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Smith,CorinneJ;Venturi,Vanessa;Quigley,MaireF;Turula,Holly;Gostick,Emma;Ladell,Kristin;Hill,BrennaJ;Himelfarb,Danielle;Quinn,KylieM;Greenaway,HuiYee;Dang,ThurstonHY;Seder,RobertA;Douek,DanielC;Hill,AnnB;Davenport,Mil
通讯作者：
Davenport,Mil

Resolving the titer of murine cytomegalovirus by plaque assay using the M2-10B4 cell line and a low viscosity overlay.

通过使用M2-10B4细胞系和低粘度覆盖层来解决鼠巨细胞病毒的滴度。