The mechanism of superantigen-mediated toxic shock: not a simple Th1 cytokine storm.

Abstract

The profound clinical consequences of Gram-positive toxic shock are hypothesized to stem from excessive Th1 responses to superantigens. We used a new superantigen-sensitive transgenic model to explore the role of TCRalphabeta T cells in responses to staphylococcal enterotoxin B (SEB) in vitro and in two different in vivo models. The proliferative and cytokine responses of HLA-DR1 spleen cells were 100-fold more sensitive than controls and were entirely dependent on TCRalphabeta T cells. HLA-DR1 mice showed greater sensitivity in vivo to two doses of SEB with higher mortality and serum cytokines than controls. When d-galactosamine was used as a sensitizing agent with a single dose of SEB, HLA-DR1 mice died of toxic shock whereas controls did not. In this sensitized model of toxic shock there was a biphasic release of cytokines, including TNF-alpha, at 2 h and before death at 7 h. In both models, mortality and cytokine release at both time points were dependent on TCRalphabeta T cells. Anti-TNF-alpha pretreatment was protective against shock whereas anti-IFN gamma pretreatment and delayed anti-TNF-alpha treatment were not. Importantly, anti-TNF-alpha pretreatment inhibited the early TNF-alpha response but did not inhibit the later TNF-alpha burst, to which mortality has previously been attributed. Splenic T cells were shown definitively to be the major source of TNF-alpha during the acute cytokine response. Our results demonstrate unequivocally that TCRalphabeta T cells are critical for lethality in toxic shock but it is the early TNF-alpha response and not the later cytokine surge that mediates lethal shock.

• Authors: Lee Faulkner, Anneli Cooper, Cristina Fantino, Daniel M Altmann, Shiranee Sriskandan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 10 Pg. 6870-7 (Nov 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 16272345 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• Enterotoxins
• HLA-DR1 Antigen
• Receptors, Antigen, T-Cell, alpha-beta
• Superantigens
• Tumor Necrosis Factor-alpha
• enterotoxin B, staphylococcal
• Galactosamine

Topics

• Animals
• Cytokines (biosynthesis)
• Enterotoxins (toxicity)
• Galactosamine (toxicity)
• HLA-DR1 Antigen (genetics, metabolism)
• Humans
• Mice
• Mice, Knockout
• Mice, Transgenic
• Receptors, Antigen, T-Cell, alpha-beta (deficiency, genetics, metabolism)
• Shock, Septic (etiology, immunology)
• Spleen (drug effects, immunology)
• Superantigens (toxicity)
• Th1 Cells (drug effects, immunology)
• Tumor Necrosis Factor-alpha (biosynthesis)