In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni.

The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

CD40/CD154 interactions are required for the optimal maturation of skin-derived APCs and the induction of helminth-specific IFN-gamma but not IL-4.

The mechanisms through which Schistosoma mansoni larvae induce Th1 rather than Th2 immune responses are not well understood. In this study, using CD154-/- mice exposed to radiation-attenuated S. mansoni larvae, we demonstrate roles for CD154/CD40 in the activation of skin-derived APCs and the development of Th1 cells in the skin-draining lymph nodes (sdLN). The presence of CD154 was important for optimal IL-12p40 and essential for Ag-specific IFN-gamma, but CD154 expression by wild-type CD4- cells was insufficient to rescue recall responses of CD4+ cells from CD154-/- mice. This defect is probably due to impaired CD40-dependent IL-12 production in vivo, because administration of anti-CD40 Ab, or rIL-12, restored IFN-gamma production by sdLN cells from CD154-/- mice. CD154 ligation of CD40 was not required for the migration of skin-derived APCs, but did have a limited role in their maturation (increased MHC II and CD86). Unexpectedly, although CD4 cells from CD154-/- mice were deficient in their ability to produce IFN-gamma, they produced significant amounts of IL-4 and IL-5 in the presence of skin-derived APCs from wild-type and CD154-/- mice. Thus, in contrast to IFN-gamma, the production of Th2-associated cytokines is (in this model) independent of CD154. We conclude that whereas the priming of Th1 responses soon after exposure to schistosome larvae is completely CD40/CD154 dependent, IL-4, IL-5, and IL-13 are independent of CD154, suggesting a dichotomy in the specific mechanisms that induce these cytokines by CD4+ cells in the sdLN.

Metabolism is required for chemotaxis to sugars in Rhodobacter sphaeroides.

Chemotaxis towards carbohydrates is mediated, in enteric bacteria, either by the transport-independent, methylation-dependent chemotaxis pathway or by transport and phosphorylation via the phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS). This study shows that Rhodobacter sphaeroides is chemotactic to a range of carbohydrates but the response involves neither the classical methyl-accepting chemotaxis protein (MCP) pathway nor the PTS transport pathway. The chemoattractant fructose was transported by a fructose-specific PTS system, but transport through this system did not appear to cause a chemotactic signal. Chemotaxis to sugars was inducible and occurred with the induction of carbohydrate transport systems and with substrate incorporation. A mutation of the glucose-6-phosphate dehydrogenase gene (zwf) inhibited chemotaxis towards substrates metabolized by this pathway although transport was unaffected. Chemotaxis to other, unrelated, chemoattractants (e.g. succinate) was unaffected. These data, in conjunction with the fact that mannitol and fructose (which utilize different transport pathways) compete in chemotaxis assays, suggest that in R. sphaeroides the chemotactic signal is likely to be generated by metabolic intermediates or the activities of the electron-transport chain and not by a cell-surface receptor or the rate or mode of substrate transport.