Early Secreted Antigen ESAT-6 of Mycobacterium Tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like receptor-2-dependent Manner

PLoS Pathog. 2011 Nov;7(11):e1002378. doi: 10.1371/journal.ppat.1002378. Epub 2011 Nov 10.

Abstract

Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2⁻/⁻) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology*
  • Antigens, Bacterial / metabolism
  • BCG Vaccine / immunology
  • Bacterial Proteins / immunology*
  • Bacterial Proteins / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Interleukin-6 / biosynthesis
  • Lung / immunology
  • Lung / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium bovis / immunology
  • Mycobacterium bovis / pathogenicity
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / metabolism
  • Mycobacterium tuberculosis / pathogenicity
  • Myeloid Differentiation Factor 88 / metabolism
  • Th1 Cells / immunology
  • Th17 Cells / immunology*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 2 / metabolism
  • Transforming Growth Factor beta / biosynthesis
  • Tuberculosis / immunology*
  • Tuberculosis / prevention & control

Substances

  • Antigens, Bacterial
  • BCG Vaccine
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Interleukin-6
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Transforming Growth Factor beta