title: Regulatory T cells and T-cell-derived IL-10 interfere with effective anti-cytomegalovirus immune response.
abstract: Cytomegalovirus (CMV) establishes lifelong chronic infection in its host with mostly asymptomatic or only mild disease, but under immunosuppressive conditions the virus can reactivate and infection can cause life-threatening disease. CMV has evolved several mechanisms to escape from host's immunity, allowing persistence of the virus. Until now, it remains elusive whether regulatory T cells (Tregs) have an impact on insufficient host immune response against the virus in this context. In the present study, we provide evidence that CD4(+)Foxp3(+) naturally occurring Tregs (nTregs) as well as CD4(+)Foxp3(-)IL-10(+)-induced Tregs (iTregs) interfere with an effective anti-mouse CMV (mCMV) immune response. Depletion of Foxp3(+) Tregs by using DEREG mice resulted in enhanced T-cell activation as measured by the expression of CD62L, granzyme B and interferon (IFN)-γ and was associated with reduced viral titers in salivary glands, the organ where mCMV mainly persists. Moreover, we identified CD4(+)Foxp3(-) T cells to produce elevated levels of the immunosuppressive cytokine IL-10 at early time points during mCMV infection. Analysis of T-cell activation and viral replication in mCMV-infected IL-10(flox/flox) × CD4-cre mice and IL-10(flox/flox) × FIC mice revealed that T-cell-specific inactivation of IL-10, but not Foxp3(+) Treg-specific IL-10 ablation alone, resulted in elevated IFN-γ production by T cells associated with a significant decrease in viral loads in salivary glands. Thus, our data illustrate a crucial role for CD4(+)Foxp3(+) nTregs as well as IL-10-producing CD4(+)Foxp3(-) iTregs in the regulation of appropriate T-cell responses and viral clearance during mCMV infection.
authors: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Nils H
authors: NH
authors: Jost
authors: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Simone
authors: S
authors: Abel
authors: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Marina
authors: M
authors: Hutzler
authors: Institute of Infection Immunology, TWINCORE, Hannover, Germany.
authors: Tim
authors: T
authors: Sparwasser
authors: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Albert
authors: A
authors: Zimmermann
authors: Institute for Immunology, TU Dresden, Dresden, Germany.
authors: Axel
authors: A
authors: Roers
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Werner
authors: W
authors: Müller
authors: Institute of Veterinary Pathology, Freie University Berlin, Berlin, Germany.
authors: Robert
authors: R
authors: Klopfleisch
authors: Institute for Virology, University Medical Center Freiburg, Albert-Ludwigs University, Freiburg, Germany.
authors: Hartmut
authors: H
authors: Hengel
authors: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Astrid M
authors: AM
authors: Westendorf
authors: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Jan
authors: J
authors: Buer
authors: 1] Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Institute for Virology, University Medical Center Freiburg, Albert-Ludwigs University, Freiburg, Germany.
authors: Wiebke
authors: W
authors: Hansen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006566:Herpesviridae Infections / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D016176:T-Lymphocyte Subsets; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; D016753:Interleukin-10