Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain

• DOI: 10.18632/oncotarget.8771
• Publication Date: 2016-04-17T02:38:37Z
• Authors: Woo Sik Kim; Jong-Seok Kim; Seung Bin Cha; Hongmin Kim; Kee Woong Kwon; So Jeong Kim; Seung Jung Han; Soo Young Choi; Sang-Nae Cho; Jong-Hwan Park; Sung Jae Shin
• Keywords: Bacterial/immunology*; Toll-Like Receptor 2/immunology; 0301 basic medicine; 570; 610; Lymphocyte Activation/immunology; Inbred C57BL; Lymphocyte Activation; multifunctional T cell; Mice; 03 medical and health sciences; Tuberculosis Vaccines/immunology*; Animals; Tuberculosis; Antigens; DC maturation; Immune response; Tuberculosis Vaccines; Antigens, Bacterial; 0303 health sciences; Immunity; Research Paper: Immunology; Dendritic Cells; Mycobacterium tuberculosis; Th1 Cells; Toll-Like Receptor 2; 3. Good health; Mice, Inbred C57BL; Toll-like receptor 2; tuberculosis; Immunology and Microbiology Section; Th1 Cells/immunology*; Tuberculosis/immunology*; Mycobacterium tuberculosis/immunology; subunit vaccine; Dendritic Cells/immunology*

Identification of vaccine target antigens (Ags) that induce Ag-specific Th1 immunity is the first step toward the development of a tuberculosis vaccine. Here, we evaluated the Mycobacterium tuberculosis (Mtb) protein Rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (DCs). Rv3628 activated DCs, increasing their expression of cell surface molecules and augmenting their production of TNF-α, IL-1β, IL-6, and IL-12p70. Rv3628 mediated these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. Rv3628-stimulated DCs induced the expansion of OVA-specific CD4+ and CD8+ T cells, which secreted IFN-γ and IL-2. Rv3628-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 Ag in samples of lung and spleen cells collected from Mtb-infected mice. Finally, an Rv3628 subunit vaccine adjuvanted with dimethyldioctadecylammonium liposomes containing monophosphoryl lipid-A caused significant reductions in bacterial counts and lung inflammation after challenge with the hyper-virulent Mtb K strain. Importantly, protective efficacy was correlated with the generation of Rv3628-specific CD4+ T cells co-producing IFN-γ, TNF-α and IL-2 and exhibiting an elevated IFN-γ recall response. Thus, Rv3628 polarizes DCs toward a Th1 phenotype and promotes protective immunity against Mtb infection.