Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome.
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.
Chau
Thu A
TA
FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, London, Ontario, Canada.
McCully
Michelle L
ML
Brintnell
William
W
An
Gary
G
Kasper
Katherine J
KJ
Vinés
Enrique D
ED
Kubes
Paul
P
Haeryfar
S M Mansour
SM
McCormick
John K
JK
Cairns
Ewa
E
Heinrichs
David E
DE
Madrenas
Joaquín
J
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis; D002473:Cell Wall / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*
D000942:Antigens, Bacterial; D007376:Interleukin-2; D008024:Ligands; D016328:NF-kappa B; D018089:Superantigens; D051195:Toll-Like Receptor 2