title: FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells.
abstract: Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigen-presenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell-induced tolerance is a T-cell-intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically analyze the involvement of FoxP3(+) regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of FoxP3(+) regulatory T cells but induced protective CD8(+) T-cell-mediated immunity instead. Regulatory T-cell-depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had up-regulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells.
authors.affiliation: Institute of Experimental Immunology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Schildknecht
authors.forename: Sabine
authors.initials: S
authors.lastname: Brauer
authors.forename: Corinne
authors.initials: C
authors.lastname: Brenner
authors.forename: Katharina
authors.initials: K
authors.lastname: Lahl
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Probst
authors.forename: Maries
authors.initials: M
authors.lastname: van den Broek
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D003713:Dendritic Cells / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016753:Interleukin-10