title: Efficient stimulation of T cell responses by human IFN-alpha-induced dendritic cells does not require Toll-like receptor triggering.
abstract: Dendritic cells (DC) can be activated by proinflammatory cytokines or upon toll-like receptor (TLR) triggering. These stimuli induce specific patterns of phenotypic modulation and gene expression profiles. We investigated whether TLR triggering represents an indispensable requirement for the induction of T cell responses by human DC generated upon culture of monocytes in the presence of granulocyte macrophage colony-stimulating factor and interferon-alpha (IFN-DC). As model stimulator we chose imidazoquinolone (3M-001), a synthetic TLR7 agonist used in the treatment of skin infections and tumors and as experimental adjuvant. At difference with DC generated upon culture of monocytes in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL-4) (IL-4-DC), IFN-DC display a semimature phenotype. Furthermore, IFN-DC, but not IL-4-DC are able to induce CD4+ and CD8+ T cell responses, in steady state, for example, in the absence of TLR triggering. 3M-001 treatment induces up-regulation of the surface expression of costimulatory molecules and "de novo" production of IL-12 and IL-6 in IFN-DC. However, TLR7 triggering fails to significantly enhance the capacity of IFN-DC to induce antigen-specific cytotoxic T lymphocytes and to stimulate allogeneic CD4+ T cells. These data indicate that TLR engagement and IL-12 production do not represent indispensable prerequisites for optimal antigen-presenting cell function in IFN-DC, qualifying these cells as powerful cellular reagents of potential use in active specific immunotherapy.
authors.affiliation: Institute for Surgical Research and Hospital Management, DBM, University Hospital, Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Bracci
authors.forename: Reto
authors.initials: R
authors.lastname: Schumacher
authors.forename: Maurizio
authors.initials: M
authors.lastname: Provenzano
authors.forename: Michel
authors.initials: M
authors.lastname: Adamina
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosenthal
authors.forename: Celia
authors.initials: C
authors.lastname: Groeper
authors.forename: Paul
authors.initials: P
authors.lastname: Zajac
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.forename: Enrico
authors.initials: E
authors.lastname: Proietti
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D051193:Toll-Like Receptors; D015847:Interleukin-4