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

[Author] 

June-Young Koh ^1 †, Min-Seok Rha ^1 2 †, Seong Jin Choi ^1 3 †, Ha Seok Lee ¹, Ji Won Han ^1 4, Heejin Nam ¹, Dong-Uk Kim ¹, Jae Geun Lee ⁵, Myoung Soo Kim ⁵, Jun Yong Park ⁶, Su-Hyung Park ¹, Dong Jin Joo ⁵, Eui-Cheol Shin ^1 7

¹ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea

² Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

³ Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea

⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea

⁵ Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

⁶ Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

⁷ The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea

[Journal] 
Journal of Hepatology Volume 77, Issue 4, October 2022, Pages 1059-1070

[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^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.