title: IFN-gamma and R-848 dependent activation of human monocyte-derived dendritic cells by Neisseria meningitidis adhesin A.
abstract: A soluble recombinant form of Neisseria meningitidis adhesin A (NadADelta351-405), proposed as a constituent of anti-meningococcal B vaccines, is here shown to specifically interact with and immune-modulate human monocyte-derived dendritic cells (mo-DCs). After priming with IFN-gamma and stimulation with NadADelta351-405, mo-DCs strongly up-regulated maturation markers CD83, CD86, CD80, and HLA-DR, secreted moderate quantities of TNF-alpha, IL-6, and IL-8, and produced a slight, although significant, amount of IL-12p70. Costimulation of mo-DCs with NadADelta351-405 and the imidoazoquinoline drug R-848, believed to mimic bacterial RNA, increased CD86 in an additive way, but strongly synergized the secretion of IL-12p70, IL-1, IL-6, TNF-alpha, and MIP-1alpha, especially after IFN-gamma priming. CD86/CD80 overexpression correlated with the occupation of high-(kd approximately 80 nM) and low-(kd approximately 4 muM) affinity binding sites for NadADelta351-405. Alternatively, secretion of IL-12p70 and TNF-alpha, IL-6, and IL-8 corresponded to the occupation of high- or low-affinity receptors, respectively. Mo-DCs matured by IFN-gamma and NadADelta351-405 supported the proliferation of naive CD4+ T lymphocytes, inducing the differentiation of both IFN-gamma and IL-4 producing phenotypes. Our data show that NadA not only is a good immunogen but is as well endowed with a proimmune, self-adjuvating, activity.
authors.affiliation: Centro Ricerche Interdipartimentale Biotecnologie Innovative and Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazzon
authors.forename: Barbara
authors.initials: B
authors.lastname: Baldani-Guerra
authors.forename: Paola
authors.initials: P
authors.lastname: Cecchini
authors.forename: Tihana
authors.initials: T
authors.lastname: Kasic
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
authors.forename: Marina
authors.initials: M
authors.lastname: de Bernard
authors.forename: Beatrice
authors.initials: B
authors.lastname: Aricò
authors.forename: Franca
authors.initials: F
authors.lastname: Gerosa
authors.forename: Emanuele
authors.initials: E
authors.lastname: Papini
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D005408:Flagellin / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007371:Interferon-gamma / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009345:Neisseria meningitidis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology