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

Nature Medicine volume 15, pages 641–648 (2009)Cite this article

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.

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Figure 1: Cytokine responses to SEE by human peripheral blood T cells and modulation of superantigen-induced IL-2 response by the staphylococcal cell wall.
Figure 2: Staphylococcal peptidoglycan (PGN)-embedded molecules modulate the human IL-2 response to superantigens.
Figure 3: The modulatory effect of staphylococcal PGN preparations is due to TLR2 signaling, probably in combination with TLR6, on APCs.
Figure 4: Staphylococcal PGN-embedded molecules modulate the superantigen-induced IL-2 response by signaling through the canonical NF-κB pathway.
Figure 5: The immunomodulatory effect of staphylococcal PGN on the T cell response to superantigens is mediated by IL-10 and ultimately apoptosis of APCs.
Figure 6: Staphylococcal PGN prevents TSS in a TLR2-dependent manner.

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Acknowledgements

We thank K.C. Kain and Z. Lu (University Health Network, Toronto) for providing mice to harvest cells for in vitro experiments and the members of the Madrenas laboratory for helpful discussions and ideas. The human B lymphoblastoid cell line LG2 was provided by E. Long (US National Institutes of Health). This work was supported by grants from the Canadian Institutes of Health Research and the Kidney Foundation of Canada. J.K.M. is a recipient of a Canadian Institutes of Health Research New Investigator Award, E.C. is a recipient of an award from the Calder Foundation and J.M. holds a Tier I Canada Research Chair in Immunobiology.

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Authors and Affiliations

  1. The FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, London, Ontario, Canada

    Thu A Chau, Michelle L McCully & Joaquín Madrenas

  2. Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada

    Michelle L McCully, Katherine J Kasper, Enrique D Vinés, S M Mansour Haeryfar, John K McCormick, Ewa Cairns, David E Heinrichs & Joaquín Madrenas

  3. Department of Medicine, The University of Western Ontario, London, Ontario, Canada

    William Brintnell, Ewa Cairns & Joaquín Madrenas

  4. Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Gary An

  5. Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada

    Paul Kubes

  6. Lawson Health Research Institute, London, Ontario, Canada

    John K McCormick

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Contributions

T.A.C., M.L.M. and W.B. performed the experiments; K.J.K. generated superantigens; E.D.V. generated bacterial strains; G.A. generated the computer model of the modulatory effect of staphylococcal peptidoglycan; P.K. provided mice for in vivo experiments; S.M.M.H., J.K.M., E.C. and D.E.H. designed and supervised experiments and edited the final manuscript; and J.M. coordinated the project, designed and supervised experiments and wrote the manuscript.

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Correspondence to Joaquín Madrenas.

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Chau, T., McCully, M., Brintnell, W. et al. Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat Med 15, 641–648 (2009). https://doi.org/10.1038/nm.1965

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