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

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.