Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome

• Published in: Nature medicine Vol. 15; no. 6; pp. 641 - 648
• Main Authors: Madrenas, Joaquín, Chau, Thu A, Brintnell, William, McCully, Michelle L, Haeryfar, S M Mansour, Cairns, Ewa, McCormick, John K, Heinrichs, David E, Kasper, Katherine J, Vinés, Enrique D, An, Gary, Kubes, Paul
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2009; Nature Publishing Group
• Subjects: Analysis; Animals; Antigen-Presenting Cells - cytology; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens; Antigens, Bacterial - immunology; Apoptosis; Bacteria; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Wall - immunology; Cellular biology; Down-Regulation - immunology; Health aspects; Humans; Immune response; Immune system; Infectious Diseases; Interleukin-2 - immunology; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Metabolic Diseases; Mice; Molecular Medicine; Mortality; Neurosciences; NF-kappa B - metabolism; Prevention; Proteins; Shock, Septic - immunology; Shock, Septic - prevention & control; Staphylococcus aureus; Staphylococcus aureus - immunology; Staphylococcus aureus infections; Superantigens - immunology; T cells; T-Lymphocytes - immunology; Toll-Like Receptor 2 - immunology; Toxic shock syndrome; Toxins; Canada
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1965

Staphylococcal superantigens are potent activators of T cells, causing toxic shock syndrome and death. But surprisingly few staphylococcal infections of humans are associated with TSS, even though the bacteria produce the superantigen toxins. Joaquin Madrenas and his colleagues report that other components of the bacteria can downregulate the superantigen-induced T cell activation, protecting the host from death by TSS. 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.