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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.

Authors
  • Kim, Woo Sik1
  • Kim, Jong-Seok1
  • Cha, Seung Bin1
  • Kim, Hongmin1
  • Kwon, Kee Woong1
  • Kim, So Jeong1
  • Han, Seung Jung1
  • Choi, Soo Young1
  • Cho, Sang-Nae1
  • Park, Jong-Hwan2
  • Shin, Sung Jae1
  • 1 Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
  • 2 Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea.
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
May 03, 2016
Volume
7
Issue
18
Pages
24962–24982
Identifiers
DOI: 10.18632/oncotarget.8771
PMID: 27097115
Source
Medline
Keywords
License
Unknown

Abstract

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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