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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.

 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 
 ONCOTARGET , Vol.7(18) : 24962-24982, 2016 
Journal Title
Issue Date
Animals ; Antigens, Bacterial/immunology* ; Dendritic Cells/immunology* ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/immunology ; Th1 Cells/immunology* ; Toll-Like Receptor 2/immunology ; Tuberculosis/immunology* ; Tuberculosis Vaccines/immunology*
DC maturation ; Immune response ; Immunity ; Immunology and Microbiology Section ; Toll-like receptor 2 ; multifunctional T cell ; subunit vaccine ; tuberculosis
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.
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5. Research Institutes (연구소) > Institute for Immunology and Immunological Disease (면역질환연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Seok(김종석)
Shin, Sung Jae(신성재) ORCID logo https://orcid.org/0000-0003-0854-4582
Cho, Sang Nae(조상래)
Cha, Seung Bin(차승빈)
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