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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24962-24982
Number of pages21
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - 2016 May 1

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Th1 Cells
Mycobacterium tuberculosis
Dendritic Cells
Immunity
Vaccines
T-Lymphocytes
Interleukin-2
Inorganic Pyrophosphatase
Tuberculosis Vaccines
Mycobacterium Infections
Subunit Vaccines
Bacterial Load
Interleukin-1
Liposomes
Interleukin-6
Pneumonia
Spleen
Phenotype
Antigens
Lung

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kim, Woo Sik ; Kim, Jong Seok ; Cha, Seung Bin ; Kim, Hongmin ; Kwon, Kee Woong ; Kim, So Jeong ; Han, Seung Jung ; Choi, Soo Young ; Cho, Sang Nae ; Park, Jong Hwan ; Shin, Sung Jae. / 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. In: Oncotarget. 2016 ; Vol. 7, No. 18. pp. 24962-24982.
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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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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. / Kim, Woo Sik; Kim, Jong Seok; Cha, Seung Bin; Kim, Hongmin; Kwon, Kee Woong; Kim, So Jeong; Han, Seung Jung; Choi, Soo Young; Cho, Sang Nae; Park, Jong Hwan; Shin, Sung Jae.

In: Oncotarget, Vol. 7, No. 18, 01.05.2016, p. 24962-24982.

Research output: Contribution to journalArticle

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AU - Kim, Woo Sik

AU - Kim, Jong Seok

AU - Cha, Seung Bin

AU - Kim, Hongmin

AU - Kwon, Kee Woong

AU - Kim, So Jeong

AU - Han, Seung Jung

AU - Choi, Soo Young

AU - Cho, Sang Nae

AU - Park, Jong Hwan

AU - Shin, Sung Jae

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AB - 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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