The role of dendritic cells in the immunopotentiating capability of meningococcal porin, PorB.

摘要

PorA and PorB are the major outer membrane proteins of the human Gram-negative pathogen, Neisseria meningitides. Neisserial porins have been shown to act as B cell mitogens and immune adjuvants. Our group has previously shown that the mechanism of the immunopotentiating capability of porin is mediated, in part, by its ability to up-regulate the T cell co-stimulatory ligand, CD86, on the surface of B cells. Due to the ability of neisserial porins to activate B cells and potentiate immune responses, we hypothesized that porin also employs the potent immune stimulatory function of dendritic cells (DCs). In this work, we examined the ability of purified N. meningitidis PorB to induce both maturation and functional activation of murine DCs. PorB induced DC maturation, as evidenced by up-regulation of surface CD40, CD86, and MHC class I and II molecules. PorB treatment enhanced the allostimulatory activity of DCs, as demonstrated by their increased activity in the mixed leukocyte reaction. Furthermore, PorB enhanced the ability of DCs to induce antigen-specific T cell activation. DCs co-treated with PorB and either ovalbumin protein (Ova) or whole chicken egg white protein induced proliferation of naive DO11.10 Ova-specific, CD4+ transgenic T cells. In addition, PorB induced secretion of the pro-inflammatory cytokines, IL-6 and TNFalpha, by DCs. As these inflammatory mediators are induced during neisserial infections, this finding suggests that neisserial porins may play a role in induction of the inflammatory process observed in meningococcal disease. PorB-induced DC maturation required expression of both myeloid differentiation factor 88 and Toll-like receptor 2 (TLR2). Our group has previously implicated these signaling molecules in PorB-induced B cell activation. Thus, PorB is a pathogen associated molecular pattern recognized by TLR2. The ability of PorB to induce DC maturation has important consequences for the activation of naive T cells and thus, the initiation of primary immune responses. Hence, the adjuvant properties of meningococcal porins can be attributed to their ability to induce DC maturation. This work sheds light on the role on meningococcal porins in the pathogenesis of meningococcal disease and reveals the mechanism(s) of their immune stimulatory activity.