title: The synthetic TLR2 agonist BPPcysMPEG leads to efficient cross-priming against co-administered and linked antigens.
abstract: The property of DC to generate effective CTL responses is influenced by TLR signaling. TLR ligands contain molecular signatures associated with pathogens, have an impact on the antigen processing and presentation by DC, and are being exploited as potential adjuvants. We hypothesized that the TLR2/6 heterodimer agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxyl polyethylene glycol (BPP), a synthetic derivative of the Mycoplasma macrophage activating lipopeptide-2, is a potent adjuvant for cross-priming against cellular antigens. Systemic administration of BPP-induced maturation of CD8alpha+ DC and CD8alpha- DC in the spleen and resulted in enhanced cross-presentation of intravenously co-administered antigen in mice. In addition, administration of BPP and cell-associated OVA generated an effective CTL response against OVA in vivo in a CD4+ T helper cell-dependent manner, but independent of IFN-alpha. Delivering antigenic peptides directly linked to BPP led to superior CTL immunity as compared to giving antigens and adjuvants admixed. In contrast to other TLR ligands, such as CpG, systemic activation of DC with BPP did not result in shut-down of antigen presentation by splenic DC subsets, although cross-priming against subsequently encountered antigens was reduced. Together, our data provide evidence that BPP is a potent stimulus to generate CTL via cross-priming.
authors.affiliation: Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: Chittappen K
authors.initials: CK
authors.lastname: Prajeeth
authors.forename: Adan Chari
authors.initials: AC
authors.lastname: Jirmo
authors.forename: Jayendra Kumar
authors.initials: JK
authors.lastname: Krishnaswamy
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzman
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.forename: Hannelore
authors.initials: H
authors.lastname: Constabel
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Georg M N
authors.initials: GM
authors.lastname: Behrens
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D006183:H-2 Antigens / Q000276:immunology; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D055666:Lipopeptides; C111390:OVA 323-339; C110366:OVA-8; D009842:Oligopeptides; D010446:Peptide Fragments; C549816:S-(2,3-bispalmitoyloxypropyl)-cysteinyl-amido-monomethoxyl polyethylene glycol; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D011092:Polyethylene Glycols; D010047:Ovalbumin