{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T22:13:29Z","timestamp":1784758409009,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2010,9,9]],"date-time":"2010-09-09T00:00:00Z","timestamp":1283990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Staphylococcal superantigens (sAgs), such as toxic shock syndrome toxin 1 (TSST-1), induce massive cytokine production, which may result in toxic shock syndrome (TSS) and sepsis. Recently, we reported that in vitro studies in human peripheral blood mononuclear cells (PBMC) do not reflect the immunological situation of the host, because after exposure to superantigens (sAgs) in vivo, mononuclear cells (MNC) leave the circulation and migrate to organs, e.g., the spleen, liver and lung. Our experimental model of choice is the rabbit because it is comparable to humans in its sensitivity to sAg. T cell activation has been assessed by lymphocyte proliferation and IL-2 gene expression after in vivo challenge with TSST-1 and the mutant antigens; expression of the genes of proinflammatory cytokines were taken as indicators for the inflammatory reaction after the combined treatment with TSST-1 and LPS. The question as to whether the biological activities of TSST-1, e.g., lymphocyte extravasation, toxicity and increased sensitivity to LPS, are mediated by T cell activation or activation by MHC II-only, are unresolved and results are contradictory. We have addressed this question by studying these reactions in vivo, with two TSST-1 mutants: one mutated at the MHC binding site (G31R) with reduced MHC binding with residual activity still present, and the other at the T cell binding site (H135A) with no residual function detectable. Here, we report that the mutant G31R induced all the biological effects of the wild type sAg, while the mutant with non-functional TCR binding did not retain any of the toxic effects, proving the pivotal role of T cells in this system.<\/jats:p>","DOI":"10.3390\/toxins2092272","type":"journal-article","created":{"date-parts":[[2010,9,19]],"date-time":"2010-09-19T09:41:46Z","timestamp":1284889306000},"page":"2272-2288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Staphylococcal Superantigen (TSST-1) Mutant Analysis Reveals that T Cell Activation Is Required for Biological Effects in the Rabbit Including the Cytokine Storm"],"prefix":"10.3390","volume":"2","author":[{"given":"Norbert","family":"Stich","sequence":"first","affiliation":[{"name":"Biomedizinische ForschungsgmbH Lazarettgasse 19\/2, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Waclavicek","sequence":"additional","affiliation":[{"name":"Biomedizinische ForschungsgmbH Lazarettgasse 19\/2, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Model","sequence":"additional","affiliation":[{"name":"Biomedizinische ForschungsgmbH Lazarettgasse 19\/2, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha M.","family":"Eibl","sequence":"additional","affiliation":[{"name":"Biomedizinische ForschungsgmbH Lazarettgasse 19\/2, A-1090 Vienna, Austria"},{"name":"Immunology Outpatient Clinic, Schwarzspanierstrasse 15, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2010,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1128\/CMR.13.1.16","article-title":"Exotoxins of Staphylococcus aureus","volume":"13","author":"Dinges","year":"2000","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1084\/jem.171.2.455","article-title":"The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells","volume":"171","author":"Marrack","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6870","DOI":"10.4049\/jimmunol.175.10.6870","article-title":"The mechanism of superantigen-mediated toxic shock: not a simple Th1 cytokine storm","volume":"175","author":"Faulkner","year":"2005","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.biocel.2006.08.009","article-title":"Streptococcus pyogenes: Insight into the function of the streptococcal superantigens","volume":"39","author":"Sriskandan","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1086\/322018","article-title":"Enhanced susceptibility to superantigen-associated streptococcal sepsis in human leukocyte antigen-DQ transgenic mice","volume":"184","author":"Sriskandan","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1086\/341828","article-title":"Lethal shock induced by streptococcal pyrogenic exotoxin A in mice transgenic for human leukocyte antigen-DQ8 and human CD4 receptors: Implications for development of vaccines and therapeutics","volume":"186","author":"Welcher","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1128\/iai.63.2.509-515.1995","article-title":"A mutation at histidine residue 135 of TSST-1 yields an immunogenic protein with minimal toxicity","volume":"63","author":"Bonventre","year":"1995","journal-title":"Infect. Immun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1093\/infdis\/174.6.1261","article-title":"A mutation at glycine residue 31 of toxic shock syndrome toxin-1 defindes a functional site critical for major histocompatibility complex class II binding and superantigenic activity","volume":"174","author":"Kum","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7544","DOI":"10.1128\/IAI.69.12.7544-7549.2001","article-title":"Temporal sequence and kinetics of proinflammatory and anti-inflammatory cytokine secretion induced by toxic shock syndrome toxin 1 in human peripheral bloodmononuclear cells","volume":"69","author":"Kum","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1086\/377308","article-title":"Vaccination with nontoxic mutant toxic shock syndrome toxin 1 protects against Staphylococcus aureus infection","volume":"188","author":"Omoe","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.4049\/jimmunol.172.3.1719","article-title":"HLA Class II polymorphisms determine responses to bacterial superantigens","volume":"172","author":"Llewelyn","year":"2004","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1128\/iai.65.7.2868-2875.1997","article-title":"Analysis of toxicity of streptococcal pyrogenic exotoxin A mutants","volume":"65","author":"Roggiani","year":"1997","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1086\/378514","article-title":"Effects of total body irradiation and cyclosporin A on the lethality of toxic shock syndrome toxin-1 in a rabbit model of toxic shock syndrome","volume":"188","author":"Dinges","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1128\/iai.36.1.123-128.1982","article-title":"Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C","volume":"36","author":"Schlievert","year":"1982","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1093\/intimm\/dxh176","article-title":"Staphylococcal enterotoxins condition cells of the innate immune system for Toll-like receptor 4 stimulation","volume":"16","author":"Rossi","year":"2004","journal-title":"Int. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1097\/01.CCM.0000060004.85054.F2","article-title":"Chronic staphylococcal enterotoxin B and LPS induce a bimodal pattern of hepatic dysfunction and injury","volume":"31","author":"Beno","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1189\/jlb.0108074","article-title":"Analysis of the early response to TSST-1 reveals V\u03b2-unrestricted extravasation, compartmentalization of the response, and unresponsiveness but not anergy to TSST-1","volume":"85","author":"Waclavicek","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1097\/01.CCM.0000194725.48928.3A","article-title":"Sepsis in European intensive care units: Results of the SOAP study","volume":"34","author":"Vincent","year":"2006","journal-title":"Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1574-695X.1999.tb01326.x","article-title":"Toxigenic bacteria and sudden infant death syndrome (SIDS): Nasopharyngeal flora during the first year of life","volume":"25","author":"Blackwell","year":"1999","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1136\/adc.70.2.95","article-title":"Antibodies to endotoxin core in sudden infant death syndrome","volume":"70","author":"Oppenheim","year":"1994","journal-title":"Arch. Dis. Child."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/infdis\/147.3.391","article-title":"Alteration of immune function by staphylococcal pyrogenic exotoxin type C: Possible role in toxic-shock syndrome","volume":"147","author":"Schlievert","year":"1983","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7169","DOI":"10.1128\/IAI.69.11.7169-7172.2001","article-title":"Comparative analysis of lipopolysaccharide-induced tumor necrosis factor alpha activity in serum and lethality in mice and rabbits pretreated with the staphylococcal superantigen toxic shock syndrome toxin 1","volume":"69","author":"Dinges","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1128\/iai.55.5.1070-1076.1987","article-title":"A rabbit model of toxic shock syndrome that uses a constant, subcutaneous infusion of toxic shock syndrome toxin 1","volume":"55","author":"Parsonnet","year":"1987","journal-title":"Infect. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1084\/jem.20052362","article-title":"Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxaemia and polymicrobial sepsis","volume":"203","author":"Huston","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1084\/jem.172.4.1091","article-title":"In vivo induction of anergy in peripheral V\u03b2 8+ T cells by Staphylococcal enterotoxin B","volume":"172","author":"Rellahan","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1182\/blood-2004-07-2523","article-title":"Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin","volume":"105","author":"Hopkins","year":"2005","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/eji.1830270405","article-title":"Superantigen and endotoxin synergize in the induction of lethal shock","volume":"27","author":"Blank","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1097\/01.CCM.0000060004.85054.F2","article-title":"Chronic Staphylococcal enterotoxin B and lipopolysaccharide induce a bimodal pattern of hepatic dysfunction and injury","volume":"31","author":"Beno","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/S0264-410X(01)00470-4","article-title":"Double mutant and formaldehyde inactivated TSST-1 as vaccine candidates for TSST-1-induced toxic shock syndrome","volume":"20","author":"Gampfer","year":"2002","journal-title":"Vaccine"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/2\/9\/2272\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:03:20Z","timestamp":1760220200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/2\/9\/2272"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,9]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2010,9]]}},"alternative-id":["toxins2092272"],"URL":"https:\/\/doi.org\/10.3390\/toxins2092272","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,9]]}}}