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

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.

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

“…An exaggerated proinflammatory response was also seen in TLR2 À/À ) WT chimeras, suggesting that the inhibitory effect was dependent on TLR2 on hematopoietic cells. These results are consistent with the inhibitory effect of ''PNG-embedded'' molecules on T-cell activation by S. aureus superantigens through the induction of IL-10 and apoptosis of antigen presenting cells [18]. Interestingly, TLR2 activation also appeared to downregulate an IL-17 response, so that in its absence, IL-17 was induced.…”

“…A similar inhibitory effect was seen with bacterial lipoproteins from Gram-positive organisms in a model of cutaneous infection, leading to re-routing of neutrophils from sites of imflammation to secondary lymphoid organs [17]. More recently, a ''PGN-embedded molecule'' that is TLR2-and TLR6-dependent was shown to inhibit IL-2 production by T cells in response to S. aureus superantigens through the induction of IL10 and apoptosis of antigen presenting cells [18].…”

“…A similar inhibitory effect was seen with bacterial lipoproteins from Gram-positive organisms in a model of cutaneous infection, leading to re-routing of neutrophils from sites of imflammation to secondary lymphoid organs [17]. More recently, a ''PGN-embedded molecule'' that is TLR2-and TLR6-dependent was shown to inhibit IL-2 production by T cells in response to S. aureus superantigens through the induction of IL10 and apoptosis of antigen presenting cells [18].The above findings suggest that LTA has a complex role in S. aureus infection, and many facets of its activity remain to be explored. The emphasis of studies so far has been on the interaction of LTA with TLR2 expressed on leukocytes, while relatively less is known about the interaction of LTA with TLR2 on other cell types.…”

“…40: 1639Immunol. -1650 Immunity to infection by S. aureus superantigens through the induction of IL-10 and apoptosis of antigen presenting cells [18]. Interestingly, TLR2 activation also appeared to downregulate an IL-17 response, so that in its absence, IL-17 was induced.…”

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

“…These levels were not that different from serum cytokine concentrations found in the iNKT cell-deficient Ja18 À/À mice (data not shown). Therefore, to accurately assess the in vivo contribution of mouse iNKT cells to SAg-induced cytokine responses, we used DR4 tg humanized mice, as in our previous studies, 32,33 which are highly sensitive to SEB. DR4 tg mice elicited robust IL-4 and IFN-g responses to aGC that reached their peak at 2 and 12 h, respectively (Figure 3a).…”