Dendritic cells and the immune response to Neisseria meningitis.

The human specific pathogen Neisseria meningitidis is a major cause of bacterial sepsis and meningitis. Effective vaccines have been developed against group A and C strains, but as yet there is no suitable vaccine available for group B N. meningitidis. The activation of Dendritic Cells (DCs) is fundamental to the initiation of an immune response. Microorganisms and microbial products induce DC maturation, including expression of co-stimulatory molecules, HLA molecules, chemokine receptors and cytokines. Maturation and migration of DCs to secondary lymphoid organs is required for the optimal induction of T-lymphocyte responses. This study investigated the importance of lipopolysaccharide (LPS) in the human pathogen N. meningitidis for DC maturation, migration and activation of T cells. DCs activated with wild type N. meningitidis increased expression of co-stimulatory molecules and HLA-DR, and produced high levels of cytokines (TNFalpha and IL-12). Expression of the chemokine receptor CCR7 was increased and DCs migrated in response to the chemokine MIPS? and showed enhanced migration through an endothelial monolayer. In co-culture experiments, T cell proliferation was enhanced by DCs that had been activated with wild type bacteria. In addition, T cell IFNgamma production was increased and IL-4/IL-13 decreased compared to controls, this is consistent with Thl differentiation. In contrast, although DCs activated by the LPS deficient isogenic mutant IpxA- increased expression of co-stimulatory molecules and HLA-DR, they produced less cytokines (TNFalpha and IL-1) than DCs stimulated with wild type bacteria and little or no IL-12. In addition, they did not increase expression of CCR7 or migrate in the presence of MIP3. DCs stimulated with IpxA- were able to activate T cells to proliferate but did not induce Thl differentiation. TLR4 has been shown to be important for responses to LPS but the Asp299Gly polymorphism described in humans was found not to affect monocyte responses to wild type N. meningitidis. These findings have important implications for vaccine design to group B N. meningitidis and suggest that in vitro responses to DCs may be used as a surrogate for in vivo immunisation experiments to test vaccine efficacy