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Previously, we identified the complete protein form of PPE39 in the hypervirulent Mycobacterium tuberculosis (Mtb) strain Beijing/K through comparative genomic analysis. PPE39 exhibited vaccine potential against Mtb challenge in a murine model. Thus, in the present study, we characterized PPE39-induced immunological features by investigating the interaction of PPE39 with dendritic cells (DCs). PPE39-treated DCs displayed reduced dextran uptake and enhanced MHC-I, MHC-II, CD80 and CD86 expression, indicating that this PPE induced phenotypic DC maturation. In addition, PPE39-treated DCs produced TNF-α, IL-6, and IL-12p70 to a similar/greater extent than lipopolysaccharide (LPS)-treated DCs in a dosedependent manner. The activating effect of PPE39 on DCs was mediated by TLR4 through downstream MAPK and NF-κB signaling pathways. Moreover, PPE39-treated DCs promoted naïve CD4+ T cell proliferation accompanied by remarkable IFN-α and IL-2 production and an increase in T-bet but not Th2-associated GATA-3 expression, suggesting that PPE39 induced Th1-type T cell responses via DC activation. Collectively, the results indicate the complete form of PPE39 is a novel TLR4 agonist that induces Th1-biased immune responses by interacting with DCs. [ABSTRACT FROM AUTHOR]