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Gastroenterology, Volume 154, Issue 4, March 2018, Pages 1047-1060. Available online 9 December 2017 | https://doi.org/10.1053/j.gastro.2017.11.277 Tumor Necrosis Factor-producing T-regulatory Cells are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

Yoon Seok Choi^{1, 2,*}, Min Kyung Jung^1,*, Jeewon Lee¹, Seong Jin Choi¹, Sung Hoon Choi³, Hyun Woong Lee⁴, Jong-Joo Lee⁵, Hyung Joon Kim⁴, Sang Hoon Ahn³, Dong Hyeon Lee⁶, Won Kim6, Su-Hyung Park⁷, Jun R. Huh⁸, Hyoung-Pyo Kim⁵, Jun Yong Park^3,#, Eui-Cheol Shin^{1, #}
¹Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

²Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea

³Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

⁴Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea

⁵Department of Environmental Medical Biology, Institute of Tropical Medicine, and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

⁶Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea

⁷Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

⁸Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA

^* These authors contributed equally to this work.

^#Correspondence to: Eui-Cheol Shin, M.D., Ph.D.; Jun Yong Park, M.D., Ph.D.

Abstract

Background and Aims

CD4⁺CD25⁺Foxp3⁺ T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors.

Methods

We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4+CD25+Foxp3+) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patters. Phenotypes of Treg cells were analyzed by flow cytometry, and an RORγt inhibitor, ML-209 was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted PBMCs and isolated Treg cells.

Results

A higher proportion of CD4⁺CD25⁺Foxp3⁺ Treg cells from patients with AHA, compared with controls, produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including upregulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared to Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients’ blood correlated with their serum level of alanine aminotransferase.

Conclusions

Treg cells from patients with AHA have altered functions, compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA.

Key words : hepatitis A virus infection; ALT; liver injury; inflammation

논문정보

TOP52018년 선정

형식Research article
게재일2017년 12월 (BRIC 등록일 2017-12-21)
연구진국내(교신)+국외 연구진
분야 의약학 > 면역의학

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