한빛사 논문
Jong Hoon Kim1,2,#, Ji Won Han1,#, Young Joon Choi1, Min-Seok Rha1, June Young Koh1, Kyung Hwan Kim1, Chang Gon Kim1, Yong Joon Lee1, A-Reum Kim1, Junsik Park1, Hong Kwan Kim3, Byung Soh Min4, Seong Il Seo5, Minyong Kang5, 6, Hye Jung Park7, Dai Hoon Han4, Soon Il Kim4, Myoung Soo Kim4, Jae Geun Lee4, Dong Hyeon Lee8, Won Kim8, Jun Yong Park7, Su-Hyung Park1,*, Dong Jin Joo4,*, Eui-Cheol Shin1,*
1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
2 Department of Dermatology, Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea
3 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
4 Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
5 Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
6 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea
7 Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
8 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
*Corresponding author : Su-Hyung Park, Dong Jin Joo, Eui-Cheol Shin
#These authors contributed equally to this work.
Abstract
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 liver cirrhosis (LC) during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A (AHA). Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative RT-PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α.
Results
Human liver CD69+CD103-CD8+ T cells exhibited a phenotype of tissue residency and terminal differentiation with HIF-2α upregulation. CD103- T cells included both hepatotropic and non-hepatotropic viruses-specific cells whereas CD103+ T cells did only hepatotropic virus-specific cells. 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. 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 AHA or LC.
Conclusions
Liver CD69+CD103-CD8+ T cells have the phenotype of tissue residency and terminally differentiation, and their effector functions depends on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology.
Key words : Human liver; CD69+CD103-CD8+ T cells; terminal differentiation; tissue residency; HIF-2α
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