Subscribe to RSS
DOI: 10.1055/s-0038-1677249
Liver-resident memory CD8+ T cells in chronic viral infection exhibit a unique transcriptional signature and are not terminally exhausted
Publication History
Publication Date:
04 January 2019 (online)
Question:
There is accumulating scientific evidence that the recently identified population of tissue-resident memory CD8+ T (TRM) cells plays a pivotal role for the combat of several viral infections, which was mostly shown for viruses replicating in mucosal tissues or secondary lymphoid organs. Due to its anatomic structure and physiologic function within the organism, the liver not only represents a unique location for tissue resident cells, but also favors a chronic outcome of viral infections. Therefore, we asked whether TRM cells develop both in acute-resolving and chronic viral infection of the liver. Moreover, we aimed at identifying and characterizing TRM cells in chronic infection as possible target for therapeutic intervention.
Methods:
Infection of C57BL/6J mice with liver-targeting adenoviruses encoding ovalbumin combined with the reporter genes GFP and luciferase either under the CMV promoter (Ad-CMV-GOL) or the hepatocyte-specific TTR promoter (Ad-TTR-GOL) caused acute-resolving or persistent liver infection, respectively. 100 naïve CD45.1+ Ovalbumin-specific OT-I CD8 T cells were transferred prior to infection in order to follow antigen-specific T cells after infection. T cell expansion, phenotype and functionality were determined by flow cytometry. T cell populations were furthermore isolated by fluorescence-activated cell sorting and subjected to RNA-sequencing.
Results:
Upon acute-resolving virus infection, we could identify a CXCR6+CD69+CD49a+ CD8+ T cell population, which was unique to the liver and exhibited properties of tissue-resident memory T cells. In a chronic liver infection model, virus-specific CD8+ T cells were not clonally deleted but expanded selectively in the liver, giving rise to a T cell population sharing characteristics with TRM cells by expressing CD69 and CXCR6. The metabolic profile concerning fatty acid and glucose uptake was consistent in both resolving and chronic infection. Moreover, CXCR6+ liver TRM cells were located in the liver sinusoids regardless of the infection outcome. However, TRM cells in the chronic infection showed reduced target cell killing capacity and high expression of inhibitory receptors. RNA-sequencing and bioinformatics analysis of liver TRM cell populations revealed unique factors driving liver residency of T cells in general, a preserved tissue-residency signature in adapted liver TRM cells and novel biomarkers to distinguish adapted from functional liver TRM cells.
Conclusions:
Adapted TRM cells are formed during chronic viral infection of the liver. They share the chemokine receptor CXCR6, the residency marker CD69, metabolic phenotype as well as the sinusoidal location with their functional counterparts in resolved liver infections. However, these cells are functionally adapted to the persisting infection. Still, the preserved tissue-residency signature of functionally adapted liver TRM cells during chronic infection suggests that these cells can be targeted for re-activation.
#