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

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.