title: Antigen-specific T-cell downregulation by human dendritic cells following blockade of NF-kappaB.
abstract: Dendritic cells (DCs) are important for presenting antigen to T cells, especially naïve T cells. It has recently been shown that blocking the transcription factor, nuclear factor kappa B (NF-kappaB) in human DCs inhibited the mixed leukocyte reaction. The aim of this study was to investigate the effect of blocking NF-kappaB in DCs during presentation of antigen to memory T cells in vitro. Peripheral blood monocytes were differentiated into immature DCs with interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and pulsed with an immunogenic tetanus toxoid peptide. Upon maturation, the antigen-pulsed DCs were highly effective in presenting antigen to autologous T cells. However, stimulation with antigen-pulsed DCs overexpressing IotakappaBetaalpha, the endogenous inhibitor of NF-kappaB, led to a significant reduction in T-cell proliferation, and decreased production of interferon-gamma, IL-4 and IL-10, whereas transforming growth factor-beta production was low throughout. There was a significant increase in apoptosis of antigen-specific T cells, even in the presence of IL-2, which was not found in resting T cells. Similar findings were observed using a proteasome inhibitor to block NF-kappaB. The effective downregulation of antigen-specific T-cell responses following blockade of NF-kappaB in DCs could be a useful approach for immunomodulating inflammatory T-cell responses.
authors.affiliation: Institute of Ophthalmology, UCL, London, UK. v.calder@ucl.ac.uk
authors.forename: V L
authors.initials: VL
authors.lastname: Calder
authors.forename: J
authors.initials: J
authors.lastname: Bondeson
authors.forename: F M
authors.initials: FM
authors.lastname: Brennan
authors.forename: B M J
authors.initials: BM
authors.lastname: Foxwell
authors.forename: M
authors.initials: M
authors.lastname: Feldmann
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000494:pharmacology; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D020672:I-kappa B Proteins; D016328:NF-kappa B; D013745:Tetanus Toxoid