4). In support of this, we found that the treatment of BCG-vaccinated mice with COX2 inhibitor in vivo significantly reduced Ag85B-specific Th17-cell responses (Fig.

4G), but not Ag85B-specific Th1-cell responses (Fig. 4H) or vaccine-induced protection in the lung following M. tuberculosis challenge (Fig. 4I). These data suggest that both in vivo and in vitro, blocking PGE2 results in reduced Th17-cell responses. Importantly, despite reduced Th17-cell responses, a competent Th1-cell response is generated, likely due to coincident loss of IL-10 production that can confer Tamoxifen ic50 vaccine-induced protection. These data suggest a role for IL-17 specifically to overcome IL-10 inhibitory effects. Consistent with a role for IL-17 in the induction of IL-12 in DCs 12, 13, we found that IL-17 treatment of BCG-exposed DCs enhanced IL-12 (Fig. 5A). Importantly, the treatment of IL-17 significantly decreased BCG-induced IL-10 production in DCs

(Fig. 5B). These data suggest that BCG exposure results in the induction of PGE2 and high levels of IL-10 that initially inhibits IL-12 production and Th1-cell BGB324 manufacturer responses in vivo (Fig. 2). Accordingly, the peak of PGE2 induction in vivo following BCG vaccination was at day 4, with significantly lower levels of PGE2 at later time points (Fig. 5C). However, BCG-induced PGE2 also mediates IL-23 induction and drives subsequent Th17-cell responses. IL-17 then induces IL-12 production and inhibits IL-10 production and mediates IFN-γ responses at later time points. Therefore, IFN-γ protein expression was not detected early, but

at later time points following BCG vaccination in vivo (Fig. 5D). In order to confirm that PGE-dependent IL-17 mediates Th1-cell responses to overcome BCG-mediated IL-10 inhibition, we depleted IL-17 in il10−/− BCG-vaccinated mice and measured Ag85B-specific Th1-cell responses in DLNs. Our data show that the depletion of IL-17 in B6 mice resulted in decreased Ag85B-specific Th1-cell response (Fig. 5E). However, depletion of IL-17 in il10−/− mice click here did not result in decreased Ag85B-specific Th1-cell responses when compared with il-10−/− BCG-vaccinated mice treated with isotype control antibody (Fig. 5E). These data suggest that IL-17 responses are required to drive Th1-cell responses, specifically to overcome IL-10-dependent Th1-cell inhibitory effects. PGE2 is critical for the induction of IL-23 responses and Th17-cell responses 18, 19, while inhibiting IL-12 responses through the production of IL-10 16. However, since PGE2-matured DCs can effectively induce IFN-γ-producing T cells 29, 30, we show that the immune system has developed means of counteracting the PGE2-mediated suppression of Th1-cell immunity. In this article, we show that the role for mycobacteria-induced PGE 2 is bifunctional since it not only induces IL-10 and limits early Th1-cell response, but also simultaneously induces IL-23 and subsequent IL-17 responses.