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

Abstract

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.

Keywords: CD161(+)CD8(+) T Cells; Chronic Hepatitis B; Liver Injury; Pathogenic Subset; TCR Repertoire.