Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner
Authors and Affiliations
Authors and Affiliations
June-Young Koh1,†, Min-Seok Rha1,2,†, Seong Jin Choi1,3,†, Ha Seok Lee1, Ji Won Han1,4, Heejin Nam1, Dong-Uk Kim1, Jae Geun Lee5, Myoung Soo Kim5, Jun Yong Park6,*, Su-Hyung Park1,*, Dong Jin Joo5,*, Eui-Cheol Shin1,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
2Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
3Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
4Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
5Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
6Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
†These authors contributed equally to this work.
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.
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 CD56hiCD161-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-associated CLD. Although CD56hiCD161-CD8+ T cells exhibit weak responsiveness to TCR stimulation, CD56hiCD161-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, CD56hiCD161-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.
In summary, the current study found a distinct CD56hiCD161-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 CD56hiCD161-CD8+ T cells in immune responses to microbial pathogens or liver immunopathology.
This study identified a distinct liver sinusoidal NK-like CD56hiCD161-CD8+ T-cell population that expands in the liver with hepatitis B virus-associated chronic liver disease. CD56hiCD161-CD8+ T cells exert NKG2C-mediated NK-like effector functions even without TCR stimulation.