IFN-gamma and R-848 dependent activation of human monocyte-derived dendritic cells by Neisseria meningitidis adhesin A

• Published in: Journal of Immunology Vol. 179; no. 6; pp. 3904 - 3916
• Main Authors: Mazzon, Cristina, Baldani-Guerra, Barbara, Cecchini, Paola, Kasic, Tihana, Viola, Antonella, de Bernard, Marina, Aricò, Beatrice, Gerosa, Franca, Papini, Emanuele
• Format: Journal Article
• Language: English
• Published: United States 15-09-2007
• Subjects: Adhesins, Bacterial - genetics; Adhesins, Bacterial - metabolism; Animals; Cell Line; CHO Cells; Cricetinae; Cricetulus; Cytokines - biosynthesis; Cytokines - genetics; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - microbiology; Flagellin - pharmacology; Humans; Imidazoles - pharmacology; Interferon-gamma - physiology; Lipopolysaccharides - pharmacology; Monocytes - cytology; Monocytes - metabolism; Neisseria meningitidis; Neisseria meningitidis - immunology; Oligodeoxyribonucleotides - pharmacology; Protein Binding - immunology; Transcriptional Activation - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.6.3904

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.