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Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis
  1. Yoon Seok Choi1,2,
  2. Jeewon Lee1,
  3. Hyun Woong Lee3,
  4. Dong-Yeop Chang1,
  5. Pil Soo Sung1,
  6. Min Kyung Jung1,
  7. Jun Yong Park4,
  8. Ja Kyung Kim4,
  9. Jung Il Lee4,
  10. Hana Park5,
  11. Jae Youn Cheong6,
  12. Kyung-Suk Suh7,
  13. Hyung Joon Kim3,
  14. June Sung Lee8,
  15. Kyung-Ah Kim8,
  16. Eui-Cheol Shin1
  1. 1Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
  2. 2Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
  3. 3Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
  4. 4Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
  5. 5Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
  6. 6Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
  7. 7Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
  8. 8Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
  1. Correspondence to Professor Eui-Cheol Shin, Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon 305-701, Republic of Korea; ecshin{at}


Objective Foxp3+CD4+CD25+ regulatory T cells (Tregs) control immune responses, but their role in acute viral hepatitis remains elusive. Herein, we investigated alteration in the peripheral blood Treg population during acute hepatitis A (AHA) and its implication in the immune-mediated liver injury.

Design The study included 71 patients with AHA, and peripheral blood mononuclear cells (PBMCs) were isolated. The suppressive activity of Treg population was determined by assessing anti-CD3/CD28-stimulated proliferation of Treg-depleted and reconstituted PBMCs. Treg cell frequency, phenotype and apoptosis in PBMCs were analysed by flow cytometry.

Results The frequency of circulating Tregs was reduced during AHA. Moreover, the suppressive activity of the total Treg pool in the peripheral blood was attenuated during AHA. Treg frequency and suppressive activity of the Treg population inversely correlated with the serum alanine aminotransferase level. Fas was overexpressed on Tregs during AHA, suggesting their susceptibility to Fas-induced apoptosis. Indeed, increased apoptotic death was observed in Tregs of patients with AHA compared with healthy controls. In addition, agonistic anti-Fas treatment further increased apoptotic death of Tregs from patients with AHA. The decreased Treg frequency and Fas overexpression on Tregs were not observed in other acute liver diseases such as acute hepatitis B, acute hepatitis C and toxic/drug-induced hepatitis.

Conclusions The size of the Treg pool was contracted during AHA, resulting from apoptosis of Tregs induced by a Fas-mediated mechanism. Decrease in Treg numbers led to reduced suppressive activity of the Treg pool and consequently resulted in severe liver injury during AHA.


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