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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 
 JOURNAL OF HEPATOLOGY, Vol.77(4) : 1059-1070, 2022-10 
Journal Title
Issue Date
CD8-Positive T-Lymphocytes* ; Immunoglobulins ; Interleukin-12 ; Interleukin-15* ; Liver ; Receptors, Antigen, T-Cell
CD8(+) T cell ; CITE-seq ; NK cell receptor ; NK-like T cell ; NKG2C ; liver
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 CD56hiCD161-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 CD56hiCD161-CD8+ T cells exhibit weak responsiveness to TCR stimulation, CD56hiCD161-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, 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.

Conclusions: In summary, the current study found a distinct CD56hiCD161-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 CD56hiCD161-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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Rha, Min-Seok(나민석) ORCID logo https://orcid.org/0000-0003-1426-7534
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
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