Decreased Frequency Of Regulatory T Cells Is Associated With Severe Immunopathology In Hepatitis A

Background: FoxP3+CD4+CD25+ regulatory T (Treg) cells are known to control immune responses against self and foreign antigens, but their role in acute viral infection remains to be elucidated. Herein, we investigated frequency of Treg cells in acute hepatitis A (AHA) and their implications in immunopathology. Methods & Materials: Forty-nine patients, who were diagnosed with AHA and hospitalized in Ilsan Paik Hospital or Chung-Ang University Hospital, were recruited in this study. All patients were seropositive for anti-HAV IgM, and all had clinical features of acute hepatitis. Peripheral blood samples at the acute stage were collected on the day of admission from all of the 49 patients. Follow-up sampling was performed at the subacute or convalescent stage. Frequency and immunophenotypes of Treg cells was analyzed in the peripheral blood using multicolor flow cytometry. Suppressive activity of Treg cell population was determined by assessing anti-CD3/CD28-stimulated proliferation of Treg-depleted PBMCs with or without adding-back of the depleted cells. Apoptosis of Treg cells was also evaluated by flow cytometery. Results: Frequency of circulating Treg cells was reduced during AHA. In addition, in vitro suppressive activity of Treg cell population was compromised, which was related with decreased frequency of Treg cells. Both decreased Treg cell frequency and attenuated suppressive activity was closely associated with the severity of liver injury. Treg cells of AHA patients contained lower percentage of Ki-67+ population and expressed higher level of Fas compared to healthy subjects. In AHA patients, apoptotic Treg cells were increased and in vitro stimulation of Fas resulted in reduction of Treg cell frequency. Conclusion: Pool size of circulating Treg cells was contracted in AHA. The contracted pool size of Treg cells was associated with attenuated suppressive activity of Treg cell population and severe immunopathology, indicating a role of Treg cells in the control of immunopathology in acute viral hepatitis.