Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner
June‐Young Koh, Min‐Seok Rha, Seong Jin Choi, Ha Seok Lee, Ji Won Han, Heejin Nam, Dong-Uk Kim, Jae Geun Lee, Myoung Soo Kim, Jun Yong Park, Su‐Hyung Park, Dong Jin Joo, Eui‐Cheol Shin
Abstract
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 hi CD161 - 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 hi CD161 - CD8 + T cells exhibit weak responsiveness to TCR stimulation, CD56 hi CD161 - 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 hi CD161 - 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 hi CD161 - 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 hi CD161 - 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.