title: 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.affiliation: Department of Infectious Diseases, Imperial College London, London, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Faulkner
authors.forename: Anneli
authors.initials: A
authors.lastname: Cooper
authors.forename: Cristina
authors.initials: C
authors.lastname: Fantino
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.forename: Shiranee
authors.initials: S
authors.lastname: Sriskandan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004768:Enterotoxins / Q000633:toxicity; D005688:Galactosamine / Q000633:toxicity; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000209:etiology* / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D018089:Superantigens / Q000633:toxicity*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004768:Enterotoxins; D015798:HLA-DR1 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal; D005688:Galactosamine