title: Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice.
abstract: We examined the formation, participation, and functional specialization of virus-reactive Foxp3(+) regulatory T cells (Tregs) in a mouse model of influenza virus infection. "Natural" Tregs generated intrathymically, based on interactions with a self-peptide, proliferated in response to a homologous viral Ag in the lungs and, to a lesser extent, in the lung-draining mediastinal lymph nodes (medLNs) of virus-infected mice. In contrast, conventional CD4(+) T cells with identical TCR specificity underwent little or no conversion to become "adaptive" Tregs. The virus-reactive Tregs in the medLNs and the lungs of infected mice upregulated a variety of molecules associated with Treg activation, as well as acquired expression of molecules (T-bet, Blimp-1, and IL-10) that confer functional specialization to Tregs. Notably, however, the phenotypes of the T-bet(+) Tregs obtained from these sites were distinct, because Tregs isolated from the lungs expressed significantly higher levels of T-bet, Blimp-1, and IL-10 than did Tregs from the medLNs. Adoptive transfer of Ag-reactive Tregs led to decreased proliferation of antiviral CD4(+) and CD8(+) effector T cells in the lungs of infected hosts, whereas depletion of Tregs had a reciprocal effect. These studies demonstrate that thymically generated Tregs can become activated by a pathogen-derived peptide and acquire discrete T-bet(+) Treg phenotypes while participating in and modulating an antiviral immune response.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Bedoya
authors.forename: Guang-Shing
authors.initials: GS
authors.lastname: Cheng
authors.forename: Abigail
authors.initials: A
authors.lastname: Leibow
authors.forename: Nardine
authors.initials: N
authors.lastname: Zakhary
authors.forename: Katherine
authors.initials: K
authors.lastname: Weissler
authors.forename: Victoria
authors.initials: V
authors.lastname: Garcia
authors.forename: Malinda
authors.initials: M
authors.lastname: Aitken
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kropf
authors.forename: David S
authors.initials: DS
authors.lastname: Garlick
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse