title: Strongly increased efficiency of altered peptide ligands by mannosylation.
abstract: Altered peptide ligands (APL) have the potential to modulate pathogenic T cell reactivity. High concentrations of APL, however, are required to achieve efficient blocking of the T cell response. We have therefore investigated whether improved delivery of APL to professional antigen-presenting cells (APC) can lead to more efficient application of such peptides. For this purpose APL were bis-mannosylated in order to facilitate their uptake by mannose receptor-positive dendritic cells (DC) in vitro. We present evidence that a 100- to 1000-fold lower concentration of bis-mannosylated APL was sufficient for complete blocking of the proliferative T cell response against the agonist peptide compared to the non-mannosylated APL. Moreover, bis-mannosylated APL were similarly effective in the inhibition of the T cell response against whole protein antigens. In contrast, unrelated, bis-mannosylated class II binding peptides were ineffective, indicating that the increased efficiency of the mannosylated APL was not due to competition for binding to class II molecules. Furthermore, a strong increase in the efficiency of presentation of APL was also observed when macrophages and peripheral blood mononuclear cells were used as APC. Thus, bis-mannosylation of APL greatly increases their potency to inhibit proliferative T cell responses. Moreover, it is likely that the use of bis-mannosylated APL will result in preferential presentation by mannose receptor-positive, professional APC. These results may be of relevance for more effective use of APL for immunoregulation in vivo.
authors.affiliation: Department of Immunohematology and Blood Bank, Leiden University Medical Center, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Agnes
authors.forename: A
authors.initials: A
authors.lastname: Tan
authors.forename: R
authors.initials: R
authors.lastname: Jordens
authors.forename: A
authors.initials: A
authors.lastname: Geluk
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
authors.forename: T
authors.initials: T
authors.lastname: Ottenhoff
authors.forename: J W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: F
authors.initials: F
authors.lastname: Koning
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D008358:Mannose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D006684:HLA-DR Antigens; D008024:Ligands; D009842:Oligopeptides; D008358:Mannose