title: TLR agonists that induce IFN-beta abrogate resident macrophage suppression of T cells.
abstract: Resident tissue macrophages (Mφs) continually survey the microenvironment, ingesting Ags and presenting them on their surface for recognition by T cells. Because these Ags can be either host cell- or pathogen-derived, Mφs must be able to distinguish whether a particular Ag should provoke an immune response or be tolerated. However, the mechanisms that determine whether Mφs promote or inhibit T cell activation are not well understood. To investigate this, we first determined the mechanism by which murine resident peritoneal Mφs suppress in vitro T cell proliferation in the absence of pathogens and then explored the effects of different pathogen-derived molecules on Mφ immunosuppression. Our results suggest that, in response to IFN-γ, which is secreted by TCR-activated T cells, resident peritoneal Mφs acquire immunosuppressive properties that are mediated by NO. However, pretreatment of Mφs with LPS or dsRNA, but not CpG or peptidoglycan, eliminates their suppressive properties, in part via the induction of autocrine-acting IFN-β. These results suggest TLR agonists that activate TRIF, and consequently induce IFN-β, but not those that exclusively signal through MyD88, abrogate the immunosuppressive properties of Mφs, and thus promote T cell expansion and elimination of invading microorganisms.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Hamilton
authors.forename: Frann
authors.initials: F
authors.lastname: Antignano
authors.forename: Anna
authors.initials: A
authors.lastname: von Rossum
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Boucher
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bennewith
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012330:RNA, Double-Stranded / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D008070:Lipopolysaccharides; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; D016899:Interferon-beta