Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A

Yoon Seok Choi, Min Kyung Jung, Jeewon Lee, Seong Jin Choi, Sung Hoon Choi, Hyun Woong Lee, Jong Joo Lee, Hyung Joon Kim, SangHoon Ahn, Dong Hyeon Lee, Won Kim, Su Hyung Park, Jun R. Huh, Hyoung Pyo Kim, Junyong Park, Eui Cheol Shin

Research output: Contribution to journalArticle

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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 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 patterns. 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 peripheral blood mononuclear cells s 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 up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with 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.

Original languageEnglish
Pages (from-to)1047-1060
Number of pages14
JournalGastroenterology
Volume154
Issue number4
DOIs
Publication statusPublished - 2018 Mar 1

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Hepatitis A
Regulatory T-Lymphocytes
Tumor Necrosis Factor-alpha
Liver
Wounds and Injuries
Th17 Cells
DNA Methylation
Blood Cells
Flow Cytometry
Cytokines
Republic of Korea
Coculture Techniques
Alanine Transaminase

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Choi, Yoon Seok ; Jung, Min Kyung ; Lee, Jeewon ; Choi, Seong Jin ; Choi, Sung Hoon ; Lee, Hyun Woong ; Lee, Jong Joo ; Kim, Hyung Joon ; Ahn, SangHoon ; Lee, Dong Hyeon ; Kim, Won ; Park, Su Hyung ; Huh, Jun R. ; Kim, Hyoung Pyo ; Park, Junyong ; Shin, Eui Cheol. / Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A. In: Gastroenterology. 2018 ; Vol. 154, No. 4. pp. 1047-1060.
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title = "Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A",
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 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 patterns. 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 peripheral blood mononuclear cells s 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 up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with 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.",
author = "Choi, {Yoon Seok} and Jung, {Min Kyung} and Jeewon Lee and Choi, {Seong Jin} and Choi, {Sung Hoon} and Lee, {Hyun Woong} and Lee, {Jong Joo} and Kim, {Hyung Joon} and SangHoon Ahn and Lee, {Dong Hyeon} and Won Kim and Park, {Su Hyung} and Huh, {Jun R.} and Kim, {Hyoung Pyo} and Junyong Park and Shin, {Eui Cheol}",
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Choi, YS, Jung, MK, Lee, J, Choi, SJ, Choi, SH, Lee, HW, Lee, JJ, Kim, HJ, Ahn, S, Lee, DH, Kim, W, Park, SH, Huh, JR, Kim, HP, Park, J & Shin, EC 2018, 'Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A', Gastroenterology, vol. 154, no. 4, pp. 1047-1060. 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. / Choi, Yoon Seok; Jung, Min Kyung; Lee, Jeewon; Choi, Seong Jin; Choi, Sung Hoon; Lee, Hyun Woong; Lee, Jong Joo; Kim, Hyung Joon; Ahn, SangHoon; Lee, Dong Hyeon; Kim, Won; Park, Su Hyung; Huh, Jun R.; Kim, Hyoung Pyo; Park, Junyong; Shin, Eui Cheol.

In: Gastroenterology, Vol. 154, No. 4, 01.03.2018, p. 1047-1060.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A

AU - Choi, Yoon Seok

AU - Jung, Min Kyung

AU - Lee, Jeewon

AU - Choi, Seong Jin

AU - Choi, Sung Hoon

AU - Lee, Hyun Woong

AU - Lee, Jong Joo

AU - Kim, Hyung Joon

AU - Ahn, SangHoon

AU - Lee, Dong Hyeon

AU - Kim, Won

AU - Park, Su Hyung

AU - Huh, Jun R.

AU - Kim, Hyoung Pyo

AU - Park, Junyong

AU - Shin, Eui Cheol

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 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 patterns. 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 peripheral blood mononuclear cells s 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 up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with 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.

AB - 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 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 patterns. 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 peripheral blood mononuclear cells s 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 up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with 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.

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DO - 10.1053/j.gastro.2017.11.277

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