Toll-like Receptor 2 Ligands on the Staphylococcal Cell Wall Downregulate Superantigen-Induced T Cell Activation and Prevent Toxic Shock Syndrome

Nat Med. 2009 Jun;15(6):641-8. doi: 10.1038/nm.1965.

Abstract

Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigens, Bacterial / immunology
  • Apoptosis
  • Cell Wall / immunology*
  • Down-Regulation / immunology
  • Humans
  • Interleukin-2 / immunology
  • Ligands
  • Lymphocyte Activation / immunology*
  • Mice
  • NF-kappa B / metabolism
  • Shock, Septic / immunology
  • Shock, Septic / prevention & control*
  • Staphylococcus aureus / immunology*
  • Superantigens / immunology*
  • T-Lymphocytes / immunology*
  • Toll-Like Receptor 2 / immunology*

Substances

  • Antigens, Bacterial
  • Interleukin-2
  • Ligands
  • NF-kappa B
  • Superantigens
  • Toll-Like Receptor 2