Table_3_Inflation vs. Exhaustion of Antiviral CD8+ T-Cell Populations in Persistent Infections: Two Sides of the Same Coin?.pdf

Persistent virus infection can drive CD8+ T-cell responses which are markedly divergent in terms of frequency, phenotype, function, and distribution. On the one hand viruses such as Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 can drive T-cell “exhaustion”, associated with upregulation of checkpoint molecules, loss of effector functions, and diminished control of viral replication. On the other, low-level persistence of viruses such as Cytomegalovirus and Adenoviral vaccines can drive memory “inflation,” associated with sustained populations of CD8+ T-cells over time, with maintained effector functions and a distinct phenotype. Underpinning these divergent memory pools are distinct transcriptional patterns—we aimed to compare these to explore the regulation of CD8+ T-cell memory against persistent viruses at the level of molecular networks and address whether dysregulation of specific modules may account for the phenotype observed. By exploring in parallel and also merging existing datasets derived from different investigators we attempted to develop a combined model of inflation vs. exhaustion and investigate the gene expression networks that are shared in these memory pools. In such comparisons, co-ordination of a critical module of genes driven by Tbx21 is markedly different between the two memory types. These exploratory data highlight both the molecular similarities as well as the differences between inflation and exhaustion and we hypothesize that co-ordinated regulation of a key genetic module may underpin the markedly different resultant functions and phenotypes in vivo—an idea which could be tested directly in future experiments.

持续性病毒感染可诱导CD8+ T细胞（CD8+ T-cell）应答，此类应答在频率、表型、功能及分布层面均呈现显著异质性。一方面，淋巴细胞脉络丛脑膜炎病毒（Lymphocytic Choriomeningitis Virus, LCMV）克隆13株可诱导T细胞“耗竭”，该过程伴随检查点分子上调、效应功能丧失以及病毒复制控制能力减弱。另一方面，巨细胞病毒（Cytomegalovirus）与腺病毒疫苗（Adenoviral vaccines）等病毒的低水平持续感染，可诱导记忆性“扩增”，该过程伴随CD8+ T细胞群体随时间持续维持，效应功能得以保留，并呈现独特表型。支撑上述两类异质性记忆库的是截然不同的转录调控模式——本研究旨在对二者进行比较，以在分子网络层面探究持续性病毒感染下CD8+ T细胞记忆的调控机制，并阐明特定基因模块的失调是否可解释所观察到的表型差异。本研究通过并行分析并整合不同研究者已获取的数据集，尝试构建记忆扩增与T细胞耗竭的整合模型，并探究两类记忆库中共有的基因表达调控网络。在此类比较中，由T-box转录因子21（Tbx21）调控的关键基因模块的协同调控模式在两类记忆细胞中存在显著差异。本探索性数据既揭示了记忆扩增与T细胞耗竭之间的分子共性，也阐明了二者的分子差异；我们提出假说：关键基因模块的协同调控或许是体内两类记忆细胞呈现显著不同功能与表型的核心机制，这一假说可在未来的实验中得到直接验证。