Kim Jong Hoon, Han Ji Won, Choi Young Joon, Rha Min-Seok, Koh June Young, Kim Kyung Hwan, Kim Chang Gon, Lee Yong Joon, Kim A Reum, Park Junsik, Kim Hong Kwan, Min Byung Soh, Seo Seong Il, Kang Minyong, Park Hye Jung, Han Dai Hoon, Kim Soon Il, Kim Myoung Soo, Lee Jae Geun, Lee Dong Hyeon, Kim Won, Park Jun Yong, Park Su-Hyung, Joo Dong Jin, Shin Eui-Cheol
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; Department of Dermatology, Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
J Hepatol. 2020 Jun;72(6):1170-1181. doi: 10.1016/j.jhep.2020.01.010. Epub 2020 Jan 24.
BACKGROUND & AIMS: Human liver CD69CD8 T cells are ~95% CD103 and ~5% CD103. Although CD69CD103CD8 T cells show tissue residency and robustly respond to antigens, CD69CD103CD8 T cells are not yet well understood.
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.
Human liver CD69CD103CD8 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 CD69CD8 effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69CD103CD8 T cells. In addition, HIF-2α expression in liver CD69CD103CD8 T cells was significantly increased in patients with acute hepatitis A or cirrhosis.
Liver CD69CD103CD8 T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69CD103CD8 T cells with HIF-2α upregulation is observed during liver pathology.
The immunologic characteristics and the role of CD69CD103CD8 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.
人类肝脏CD69⁺CD8⁺ T细胞约95%为CD103⁺，约5%为CD103⁻。尽管CD69⁺CD103⁺CD8⁺ T细胞表现出组织驻留性且能强烈应答抗原，但CD69⁺CD103⁻CD8⁺ T细胞尚未得到充分了解。
在肝移植期间，从健康活体供体和肝硬化受体处采集肝脏灌流液和配对的外周血。从甲型急性肝炎患者处获取肝脏组织。通过流式细胞术进行表型和功能分析。通过微阵列和定量逆转录PCR确定基因表达谱。使用PT - 2385抑制缺氧诱导因子（HIF）-2α。
人类肝脏CD69⁺CD103⁺CD8⁺ T细胞表现出HIF - 2α上调，具有组织驻留和终末分化的表型。CD103⁺细胞包含非嗜肝病毒特异性T细胞以及嗜肝病毒特异性T细胞，但CD103⁻细胞仅表现出嗜肝病毒特异性。尽管单个CD103⁻细胞作为效应细胞比CD103⁺细胞弱，但在T细胞受体或白细胞介素-15刺激后，它们仍是肝脏中主要的CD69⁺CD8⁺效应细胞群体，细胞死亡较少而存活。一种HIF - 2α抑制剂可抑制CD69⁺CD103⁺CD8⁺ T细胞的效应功能和存活。此外，甲型急性肝炎或肝硬化患者肝脏CD69⁺CD103⁺CD8⁺ T细胞中的HIF - 2α表达显著增加。
肝脏CD69⁺CD103⁺CD8⁺ T细胞是组织驻留且终末分化的，其效应功能依赖于HIF - 2α。此外，在肝脏病理过程中观察到肝脏CD69⁺CD103⁺CD8⁺ T细胞被激活且HIF - 2α上调。
人类肝脏CD8⁺ T细胞的主要群体CD69⁺CD103⁺CD8⁺ T细胞的免疫特征和作用尚不清楚。我们的研究表明，这些T细胞具有终末分化的组织驻留表型，其效应功能依赖于转录因子HIF - 2α。此外，这些T细胞在肝脏病理状态下被激活并表达更高水平的HIF - 2α，表明它们在肝脏组织免疫应答和人类肝脏疾病发病机制中起重要作用。
