Background & aims: CD161-expressing CD8^{+} T cells consist of mucosal-associated invariant T cells with semi-invariant T-cell receptor (TCR) use and non-mucosal-associated invariant T CD161^{+}CD8^{+} T cells with polyclonal TCR repertoire. Although CD161^{+}CD8^{+} T cells are enriched in liver and embrace hepatitis B virus (HBV)-specific T cells in chronic hepatitis B (CHB) patients, their roles in disease progression remain poorly understood. This study aimed to decipher their profiling and dynamic changes during chronic HBV infection.
Methods: Blood samples from 257 CHB patients and nontumor liver specimens from 73 HBV-positive patients were analyzed for CD161^{+}CD8^{+} T-cell characterization by flow cytometry, TCR repertoire determination, transcriptomic analyses, and cell experiments.
Results: CD161^{+}CD8^{+} T cells were increased and hyperactivated in patients, while positive correlation between the CD161^{+}CD8^{+} T-cell ratio and HBV-DNA level suggested this was insufficient to control HBV replication. The overlap of complementarity determining region 3 sequences supported the switch between CD161^{-}CD8^{+} and CD161^{+}CD8^{+} populations. Although CD161^{+}CD8^{+} T cells were endowed with innateness phenotype and enhanced antiviral capacity, the population from patients had impaired type I cytokine production, and increased interleukin 17 and granzyme B secretion. The increased CD161^{+}CD8^{+} T cells and their increased granzyme B secretion correlated positively with inflammation-associated liver injury. Hepatic CD161^{+}CD8^{+} T cells showed neutrophil-related pathogenic potential because they had increased transcript signatures and proinflammatory cytokine production in neutrophil recruitment- and response-related pathways that changed consistently in the injured liver.
Conclusions: Our results highlight the reduced antiviral potency but increased pathogenic potential of CD161^{+}CD8^{+} T cells in CHB patients, supporting CD161 expression as a marker of pathogenic CD8^{+} T subset and the intervention target for liver injury.
【저자키워드】 Liver injury, Chronic Hepatitis B, CD161(+)CD8(+) T Cells, Pathogenic Subset, TCR Repertoire.,