A novel Th1-type T-cell immunity-biasing effect of malate dehydrogenase derived from Mycobacterium avium subspecies paratuberculosis via the activation of dendritic cells

Woo Sik Kim, Jong Seok Kim, Min Kyoung Shin, SungJae Shin

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative pathogen of Johne's disease in ruminants, characterized by chronic granulomatous enteritis; it also has zoonotic potential and is associated with Crohn's disease in humans. A better understanding of the mycobacterial antigens and their roles in the host immune response may facilitate the rational design of control strategies, including the development of effective vaccines and diagnostic tools. However, the functional roles of a large proportion of MAP antigens involved in modulating the host immune response remain unknown. In this study, an immunological role of MAP malate dehydrogenase (MDH, MAP2541c), an antigen that is upregulated in stress culture conditions, such as nutrient starvation and hypoxia, in polarizing naïve CD4 + /CD8 + T cells toward Th1-biased T-cell immunity via the activation of dendritic cells (DCs) was identified. DCs treated with MAP MDH displayed characteristics of the activated and mature immune status, with augmented expression of cell surface molecules and pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12p70, but not IL-10, along with a dose-dependent decrease in the antigen uptake capacity. A mechanistic investigation revealed that the observed DC maturation is mediated by the activation of JNK, ERK, and p38 MAP kinases, and the NF-κB signaling pathway. Notably, DCs activated by MAP MDH treatment promoted naïve CD4 + /CD8 + T cell proliferation; in particular, they effectively polarized naïve CD4 + T cells to secrete IFN-γ and IL-2 and activate T-bet, but, unlike the LPS control, did not influence IL-5 and GATA-3. These results indicated that MAP MDH has the potential to induce the Th1 cell response via DC activation. Collectively, our data demonstrated that MAP MDH is a novel immunostimulatory antigen that drives Th1-biased T cell polarization via interactions with DCs, suggesting that MDP MDH has the potential to be an effective MAP vaccine antigen target and diagnostic marker.

Original languageEnglish
Pages (from-to)14-22
Number of pages9
JournalCytokine
Volume104
DOIs
Publication statusPublished - 2018 Apr 1

Fingerprint

Mycobacterium avium subsp. paratuberculosis
Malate Dehydrogenase
Th1 Cells
T-cells
Dendritic Cells
Immunity
Chemical activation
T-Lymphocytes
Antigens
Vaccines
Crohn Disease
Interleukin-5
Cell proliferation
Pathogens
Interleukin-1
Interleukin-10
Nutrients
Interleukin-2
Paratuberculosis
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

Cite this

@article{ee943249c5be4152bd5e3dcba456c0d9,
title = "A novel Th1-type T-cell immunity-biasing effect of malate dehydrogenase derived from Mycobacterium avium subspecies paratuberculosis via the activation of dendritic cells",
abstract = "Mycobacterium avium subspecies paratuberculosis (MAP) is the causative pathogen of Johne's disease in ruminants, characterized by chronic granulomatous enteritis; it also has zoonotic potential and is associated with Crohn's disease in humans. A better understanding of the mycobacterial antigens and their roles in the host immune response may facilitate the rational design of control strategies, including the development of effective vaccines and diagnostic tools. However, the functional roles of a large proportion of MAP antigens involved in modulating the host immune response remain unknown. In this study, an immunological role of MAP malate dehydrogenase (MDH, MAP2541c), an antigen that is upregulated in stress culture conditions, such as nutrient starvation and hypoxia, in polarizing na{\"i}ve CD4 + /CD8 + T cells toward Th1-biased T-cell immunity via the activation of dendritic cells (DCs) was identified. DCs treated with MAP MDH displayed characteristics of the activated and mature immune status, with augmented expression of cell surface molecules and pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12p70, but not IL-10, along with a dose-dependent decrease in the antigen uptake capacity. A mechanistic investigation revealed that the observed DC maturation is mediated by the activation of JNK, ERK, and p38 MAP kinases, and the NF-κB signaling pathway. Notably, DCs activated by MAP MDH treatment promoted na{\"i}ve CD4 + /CD8 + T cell proliferation; in particular, they effectively polarized na{\"i}ve CD4 + T cells to secrete IFN-γ and IL-2 and activate T-bet, but, unlike the LPS control, did not influence IL-5 and GATA-3. These results indicated that MAP MDH has the potential to induce the Th1 cell response via DC activation. Collectively, our data demonstrated that MAP MDH is a novel immunostimulatory antigen that drives Th1-biased T cell polarization via interactions with DCs, suggesting that MDP MDH has the potential to be an effective MAP vaccine antigen target and diagnostic marker.",
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A novel Th1-type T-cell immunity-biasing effect of malate dehydrogenase derived from Mycobacterium avium subspecies paratuberculosis via the activation of dendritic cells. / Kim, Woo Sik; Kim, Jong Seok; Shin, Min Kyoung; Shin, SungJae.

In: Cytokine, Vol. 104, 01.04.2018, p. 14-22.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel Th1-type T-cell immunity-biasing effect of malate dehydrogenase derived from Mycobacterium avium subspecies paratuberculosis via the activation of dendritic cells

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AB - Mycobacterium avium subspecies paratuberculosis (MAP) is the causative pathogen of Johne's disease in ruminants, characterized by chronic granulomatous enteritis; it also has zoonotic potential and is associated with Crohn's disease in humans. A better understanding of the mycobacterial antigens and their roles in the host immune response may facilitate the rational design of control strategies, including the development of effective vaccines and diagnostic tools. However, the functional roles of a large proportion of MAP antigens involved in modulating the host immune response remain unknown. In this study, an immunological role of MAP malate dehydrogenase (MDH, MAP2541c), an antigen that is upregulated in stress culture conditions, such as nutrient starvation and hypoxia, in polarizing naïve CD4 + /CD8 + T cells toward Th1-biased T-cell immunity via the activation of dendritic cells (DCs) was identified. DCs treated with MAP MDH displayed characteristics of the activated and mature immune status, with augmented expression of cell surface molecules and pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12p70, but not IL-10, along with a dose-dependent decrease in the antigen uptake capacity. A mechanistic investigation revealed that the observed DC maturation is mediated by the activation of JNK, ERK, and p38 MAP kinases, and the NF-κB signaling pathway. Notably, DCs activated by MAP MDH treatment promoted naïve CD4 + /CD8 + T cell proliferation; in particular, they effectively polarized naïve CD4 + T cells to secrete IFN-γ and IL-2 and activate T-bet, but, unlike the LPS control, did not influence IL-5 and GATA-3. These results indicated that MAP MDH has the potential to induce the Th1 cell response via DC activation. Collectively, our data demonstrated that MAP MDH is a novel immunostimulatory antigen that drives Th1-biased T cell polarization via interactions with DCs, suggesting that MDP MDH has the potential to be an effective MAP vaccine antigen target and diagnostic marker.

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