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Functions of human liver CD69 + CD103 - CD8 + T cells depend on HIF-2α activity in healthy and pathologic livers

 Jong Hoon Kim  ;  Ji Won Han  ;  Young Joon Choi  ;  Min-Seok Rha  ;  June Young Koh  ;  Kyung Hwan Kim  ;  Chang Gon Kim  ;  Yong Joon Lee  ;  A Reum Kim  ;  Junsik Park  ;  Hong Kwan Kim  ;  Byung Soh Min  ;  Seong Il Seo  ;  Minyong Kang  ;  Hye Jung Park  ;  Dai Hoon Han  ;  Soon Il Kim  ;  Myoung Soo Kim  ;  Jae Geun Lee  ;  Dong Hyeon Lee  ;  Won Kim  ;  Jun Yong Park  ;  Su-Hyung Park  ;  Dong Jin Joo  ;  Eui-Cheol Shin 
 JOURNAL OF HEPATOLOGY, Vol.72(6) : 1170-1181, 2020-06 
Journal Title
Issue Date
CD69(+)CD103(-)CD8(+) T cells ; HIF-2α ; Human liver ; Terminal differentiation ; Tissue residency
Background & aims: Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. Methods: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. Results: Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. Conclusions: Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. Lay summary: The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 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
Kim, Soon Il(김순일) ORCID logo https://orcid.org/0000-0002-0783-7538
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Park, Hye Jung(박혜정) ORCID logo https://orcid.org/0000-0002-1862-1003
Lee, Jae Geun(이재근) ORCID logo https://orcid.org/0000-0002-6722-0257
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
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