title: Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice.
abstract: The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4(+) Foxp3(+) regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes.
  
  
  CONCLUSIONS
  Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance.
authors.affiliation: Institutes of Virology, Immunology, and Hygiene, Technische Universität München / Helmholtz Zentrum München, München, Germany.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Stross
authors.forename: Johannes
authors.initials: J
authors.lastname: Günther
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.forename: Theresa
authors.initials: T
authors.lastname: Asen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Graf
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
mesh_terms: D000208:Acute Disease; D000818:Animals; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology* / Q000821:virology*; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse