Increased Non-MAIT CD161⁺CD8⁺ T Cells Display Pathogenic Potential in Chronic HBV Infection

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.

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.

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.

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.