Distinct NK-like characteristics of liver sinusoidal CD56$^{hi}$CD161$^-$CD8$^+$ T Cells

Abstract

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. We obtained liver sinusoidal mononuclear cells from the liver perfusate of healthy donors and recipients with hepatitis B virus (HBV)-associated chronic liver disease (CLD) during liver transplantation. We performed a CITE-seq analysis of liver sinusoidal CD45$^+$ cells in combination with TCR-seq and flow cytometry to examine the phenotypes and functions of liver sinusoidal CD8$^+$ T cells. We identified a distinct CD56$^{hi}$CD161$^-$CD8$^+$ T-cell population characterized by NK-related gene expression and uniquely restricted TCR repertoire, and their frequency among the liver sinusoidal CD8$^+$ T-cell population was significantly increased in patients with HBV-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, KIRs, 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. In summary, the current study found a distinct CD56$^{hi}$CD161$^-$CD8$^+$ T-cell population characterized by NK-like activation by 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.