Dysfunctional liver-resident CXCR6+ CD8 T cells during persistent viral liver infection

Background A strong CD8 T cell response is crucial to eliminate hepatotropic viral infections such as hepatitis B virus infection. Contrastingly, a weak T cell response characterizes persistent viral infection of the liver. We aimed at pinpointing the mechanism mediating dysfunctionality in liver-resident CD8 T cells during persistent viral liver infection.

Methods Adenovirus-based gene transfer (coding for ovalbumin or the HBV genome) was used to establish persistent or acute-resolved infection. Naïve (CD44negCD62Lhi) virus-specific CD8 T cells bearing a congenic marker were transferred before infection. Cells were analyzed at different time points for phenotypic and functional characterization and RNAseq.

Results We identified two distinct virus-specific hepatic T cell populations after acute-resolved infection, i. e. CX3CR1+ and CXCR6+CD69+ CD8 T cells. In persistent infection, mainly CXCR6+CD69+ liver-resident CD8 T cells were found. Liver CXCR6+CD69+ CD8 T cells expressed a tissue-residency gene signature, but in the persistent infection lacked anti-viral effector functions, i. e. determined by loss of effector cytokine production and cytotoxicity. Using RNAseq and bioinformatic analyses, we defined a single transcriptional pathway distinguishing dysfunctional CXCR6+CD69+ T cells in persistent infection from effector memory T cells after resolved infection.

Conclusion The identification of a single transcription factor distinguishing effector memory from dysfunctional tolerized virus-specific resident CD8 T cells in preclinical models of persistent expression of ovalbumin and HBV points towards a liver-specific mechanism mediating immune tolerance during persistent hepatocyte infection.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022