Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Front Cell Infect Microbiol. 2016 Nov 18;6:147. doi: 10.3389/fcimb.2016.00147. eCollection 2016.

Abstract

TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2-/- mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

Keywords: MHC II; Mycobacterium tuberculosis; Rv1061c; TLR2; apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / drug effects*
  • Apoptosis / drug effects*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / pharmacology*
  • Cell Line
  • Cell Wall / chemistry
  • DNA, Bacterial
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genes, Bacterial / genetics
  • Histocompatibility Antigens Class II / drug effects*
  • Humans
  • Interferon-gamma / drug effects
  • Lipoproteins / genetics*
  • Lipoproteins / metabolism
  • Macrophages / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium smegmatis
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / metabolism*
  • Nuclear Proteins / drug effects
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Cell Surface / physiology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology*
  • Signal Transduction / drug effects
  • Survival Analysis
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptors / classification
  • Toll-Like Receptors / metabolism
  • Trans-Activators / drug effects
  • Tuberculosis / microbiology

Substances

  • Bacterial Proteins
  • DNA, Bacterial
  • Histocompatibility Antigens Class II
  • Lipoproteins
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Trans-Activators
  • Interferon-gamma