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Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis

 Ja Kyung Kim  ;  Jung Il Lee  ;  Min Kyung Jung  ;  Pil Soo Sung  ;  Dong Yeop Chang  ;  Hyun Woong Lee  ;  Jeewon Lee  ;  Yoon Seok Choi  ;  Jun Yong Park  ;  Hana Park  ;  Jae Youn Cheong  ;  Kyung Suk Suh  ;  Hyung Joon Kim  ;  June Sung Lee  ;  Kyung Ah Kim  ;  Eui Cheol Shin 
 Gut, Vol.64(8) : 1303-1313, 2015 
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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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김자경(Kim, Ja Kyung) ORCID logo https://orcid.org/0000-0001-5025-6846
박준용(Park, Jun Yong) ORCID logo https://orcid.org/0000-0001-6324-2224
이정일(Lee, Jung Il) ORCID logo https://orcid.org/0000-0002-0142-1398
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