Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner

Background & Aims: The liver provides a unique niche of lymphocytes enriched with a large proportion of innate-like T cells. However, the heterogeneity and functional characteristics of the hepatic T-cell population remain to be fully elucidated. Methods: We obtained liver sinusoidal mononuclear cells from the liver perfusate of healthy donors and recipients with HBV-associated chronic liver disease (CLD) during liver transplantation. We performed a CITE-seq analysis of liver sinusoidal CD45⁺ cells in combination with T cell receptor (TCR)-seq and flow cytometry to examine the phenotypes and functions of liver sinusoidal CD8⁺ T cells. Results: We identified a distinct CD56^hiCD161^-CD8⁺ T-cell population characterized by natural killer (NK)-related gene expression and a uniquely restricted TCR repertoire. The frequency of these cells among the liver sinusoidal CD8⁺ T-cell population was significantly increased in patients with HBV-associated CLD. Although CD56^hiCD161^-CD8⁺ T cells exhibit weak responsiveness to TCR stimulation, CD56^hiCD161^-CD8⁺ T cells highly expressed various NK receptors, including CD94, killer immunoglobulin-like receptors, and NKG2C, and exerted NKG2C-mediated NK-like effector functions even in the absence of TCR stimulation. In addition, CD56^hiCD161^-CD8⁺ T cells highly respond to innate cytokines, such as IL-12/18 and IL-15, in the absence of TCR stimulation. We validated the results from liver sinusoidal CD8⁺ T cells using intrahepatic CD8⁺ T cells obtained from liver tissues. Conclusions: In summary, the current study found a distinct CD56^hiCD161^-CD8⁺ T-cell population characterized by NK-like activation via TCR-independent NKG2C ligation. Further studies are required to elucidate the roles of liver sinusoidal CD56^hiCD161^-CD8⁺ T cells in immune responses to microbial pathogens or liver immunopathology. Lay summary: The role of different immune cell populations in the liver is becoming an area of increasing interest. Herein, we identified a distinct T-cell population that had features similar to those of natural killer (NK) cells – a type of innate immune cell. This distinct population was expanded in the livers of patients with chronic liver disease and could thus have pathogenic relevance.