6C). Nevertheless, splenocytes from mice injected with DCs matured with the VSGs significantly downregulated IL-17 production comparable to the T-cell cytokine profile of TNF-DC-treated animals. Mice treated with MiTat-matured DCs, however, Selleckchem PD0325901 were not able to block the nonprotective IFN-γ production as TNF-DC-treated animals, but in addition, retained high production of the disease-preventing cytokines IL-13 and IL-10 (Fig. 6C). Moreover, repetitive injections of differentially

matured DCs did not alter the frequencies of FoxP3-expressing Treg cells in spleens of EAE-diseased mice (Supporting Information Fig. 5D). This suggests that semi-mature DCs regulate EAE by protective mechanisms other than CD25+ FoxP3+ Treg-cell induction. In sum, the partial DC maturation stages were all equally effective in creating a protective Th2/Tr1-cell environment, which was able to block the Th1/Th17-cell mediated EAE. In this study, we showed that similar partial maturation stages of DCs can be achieved with the proinflammatory cytokine TNF and the T. brucei antigens selleck chemicals mfVSG and MiTat1.5 sVSG. Our data further indicate that low concentrations of pathogen-derived

TLR-mediated stimuli program DCs similarly to the inflammatory cytokine TNF for the differentiation toward an inflammatory, semi-mature DC phenotype. These partial DC maturation stages were able to induce Th2-cell priming in vitro and in vivo and induced only quantitative differences in the extent of Th2-cell differentiation. Moreover, these Th2-cell signatures did not differ in their intrinsic quality to heal autoimmune diseases such as EAE and had no influence on allergic asthma. These data have important implications for the understanding of parasitic immune

evasion, the design of vaccines and provide further insights how DC maturation signatures critically contribute to the differentiation of defined Th-cell subsets. The stimulus LPS triggers DC maturation through TLR4 ligation and directs Th-cell differentiation toward Th1-cells. Less is known which PRRs drive Th2-cell associated immune responses. Recent reports suggest that house dust mite allergens initiate asthmatic GNE-0877 inflammation by signaling through the TLR4 receptor complex in part by LPS contamination 45, 46. Our data show that the T. brucei antigen MiTat1.5 sVSG-conditioned DCs to produce IL-6 and IL-1β, which is dependent on TLR4 and the adaptor molecule MyD88. A novel TLR4-mediated signaling pathway was identified in which TLR4 stimuli trigger a rapid increase in intracellular cAMP followed by translocation of the transcription factor CREB and IL-6 production 47. Further investigation is needed to address whether MiTat1.5 sVSG activation of DCs is accompanied with an intracellular cAMP rise and CREB transcription factor translocation. The T. brucei AnTat1.