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Streptococcus Pyogenes Exotoxins I and J Immunological and Biochemical Characterization of Streptococcal Pyrogenic Exotoxins I and J (SPE-I and SPE-J) from Streptococcus pyogenes This information is current as of September 28, 2021. Thomas Proft, Vickery L. Arcus, Vanessa Handley, Edward N. Baker and John D. Fraser J Immunol 2001; 166:6711-6719; ; doi: 10.4049/jimmunol.166.11.6711 http://www.jimmunol.org/content/166/11/6711 Downloaded from References This article cites 47 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/166/11/6711.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunological and Biochemical Characterization of Streptococcal Pyrogenic Exotoxins I and J (SPE-I and SPE-J) from Streptococcus pyogenes1 Thomas Proft,* Vickery L. Arcus,† Vanessa Handley,* Edward N. Baker,† and John D. Fraser2* Recently, we described the identification of novel streptococcal superantigens (SAgs) by mining the Streptococcus pyogenes M1 genome database at Oklahoma University. Here, we report the cloning, expression, and functional analysis of streptococcal pyrogenic exotoxin (SPE)-J and another novel SAg (SPE-I). SPE-I is most closely related to SPE-H and staphylococcal enterotoxin I, whereas SPE-J is most closely related to SPE-C. Recombinant forms of SPE-I and SPE-J were mitogenic for PBL, both reaching half maximum responses at 0.1 pg/ml. Evidence from binding studies and cell aggregation assays using a human B-lymphoblastoid cell line (LG-2) suggests that both toxins exclusively bind to the polymorphic MHC class II ␤-chain in a zinc-dependent mode but Downloaded from not to the generic MHC class II ␣-chain. The results from analysis by light scattering indicate that SPE-J exists as a dimer in solution above concentrations of 4.0 mg/ml. Moreover, SPE-J induced a rapid homotypic aggregation of LG-2 cells, suggesting that this toxin might cross-link MHC class II molecules on the cell surface by building tetramers of the type HLA-DR␤–SPE-J–SPE- J–HLA-DR␤. SPE-I preferably stimulates T cells bearing the V␤18.1 TCR, which is not targeted by any other known SAg. SPE-J almost exclusively stimulates V␤2.1 T cells, a V␤ that is targeted by several other streptococcal SAgs, suggesting a specific role for this T cell subpopulation in immune defense. Despite a primary sequence diversity of 51%, SPE-J is functionally indistin- http://www.jimmunol.org/ guishable from SPE-C and might play a role in streptococcal disease, which has previously been addressed to SPE-C. The Journal of Immunology, 2001, 166: 6711–6719. treptococcus pyogenes is a major human pathogenic bac- levels of the cytokines TNF-␣ and IL-1␤ and of T cell mediators, terium that causes a wide range of diseases including acute such as IL-2 and IFN-␥ (8, 17–19). Stonsillitis, streptococcal toxic shock syndrome, scarlet fe- Thus far, four streptococcal SAgs have been identified after pu- ver, necrotizing fasciitis, cellulitis, and bacteremia (1–4). This rification from cell culture supernatants. These are SPE-A (20), Gram-positive bacterium produces a variety of exotoxins, SPE-C (21), streptococcal mitogenic exotoxin Z (SMEZ) (22), and known as streptococcal pyrogenic exotoxins (SPEs),3 which are streptococcal SAg (SSA) (23). Recently, two novel sag genes by guest on September 28, 2021 believed to be involved in pathogenicity or virulence. Together (spe-g and spe-h) and one incomplete sag gene (spe-j) have been with the staphylococcal enterotoxins (SEs) and the toxic shock identified by screening the incomplete S. pyogenes M1 genome syndrome toxin (TSST) produced by Staphylococcus aureus, database at Oklahoma University (24, 25). The predicted superan- they build a larger family of structurally related proteins (5–7). tigenic properties of SPE-G and SPE-H have been confirmed by These proteins are also known as superantigens (SAgs), due to biochemical and immunological analysis of the corresponding re- their ability to stimulate large populations of T cells (8, 9). In combinant proteins (24). contrast to conventional Ags, SAgs are not processed inside SPE-B and SPE-F were originally added to the list of strepto- APCs, but instead directly bind to the MHC class II protein coccal SAgs, but this has been controversial. Both proteins are outside the Ag binding groove (10–14). Simultaneously, they genetically unrelated to the streptococcal and staphylococcal bind to all TCRs bearing particular V␤ regions (15, 16). This SAgs, and the superantigenic properties of SPE-B (streptococcal trimolecular complex subsequently cross-links a large number cysteine protease) were shown to be due to contamination (15). of APCs and T cells resulting in the production of high systemic There are now crystal structures for 11 SAgs: SPE-A (26), SPE-C (27), SPE-H (28), SMEZ-2 (28), and SSA (29), and the staphylococcal toxins SEA (30), SEB (31), SEC2 (32), SED (33), SEH (34), and TSST (35). Despite the limited primary sequence *Division of Molecular Medicine and †School of Biological Sciences, University of homology (sometimes Ͻ25%), all structures show a conserved Auckland, Auckland, New Zealand ␤ folding pattern, comprising a NH2-terminal -barrel globular do- Received for publication January 10, 2001. Accepted for publication March 27, 2001. main and a COOH-terminal globular domain based on a ␤-grasp The costs of publication of this article were defrayed in part by the payment of page motif. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. All examined staphylococcal SAgs, as well as the streptococcal SSA and SPE-A, have a generic binding site for the invariant 1 This work was supported by the Health Research Council of New Zealand. ␣-chain of MHC class II located in the NH -terminal domain (10, 2 Address correspondence and reprint requests to Prof. John D. Fraser, Division of 2 Molecular Medicine, School of Medicine, University of Auckland, Private Bag 19). In contrast, SPE-C, SPE-G, SPE-H, and all SMEZ variants 92019, Auckland, New Zealand. E-mail address: [email protected] bind the polymorphic MHC class II ␤-chain, probably mediated by 3 Abbreviations used in this paper: SPE, streptococcal pyrogenic exotoxin; SE, staph- a zinc coordination complex between three SAg residues and the ylococcal enterotoxin; TSST, toxic shock syndrome toxin; SAg, superantigen; SMEZ, ␤ streptococcal mitogenic exotoxin Z; SSA, streptococcal SAg; RPMI-10, RPMI 1640 highly conserved His81 of the HLA-DR1 -chain (24, 27, 36). with 10% FCS; SCRs, structurally conserved regions; pI, isoelectric point. SEA and SEE combine both binding modes to cross-link MHC Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 6712 CHARACTERIZATION OF STREPTOCOCCAL PYROGENIC EXOTOXINS I AND J class II molecules. This appears to be a requirement for inflam- Toxin proliferation assay matory cytokine production (37, 38). SPE-C possesses an alterna- Human PBLs were purified from the blood of a healthy donor by His- tive mechanism for cross-linking MHC class II by forming ho- topaque Ficoll (Amersham, Arlington Heights, IL) fractionation. The PBL 5 modimers via the NH2-terminal domains (27, 36). were incubated in 96-well round-bottom microtiter plates at 10 cells per Recently, the S. pyogenes M1 genome sequencing project was well with RPMI-10 (RPMI 1640 with 10% FCS) containing varying dilu- ␮ 3 completed. A repeated screen of this database identified the miss- tions of recombinant toxins. After 3 days, 0.1 Ci [ H]thymidine was Ј added to each well, and cells were incubated for another 24 h. Cells were ing 5 end of the spe-j gene and another novel sag gene that is harvested and counted on a scintillation counter. identical with spe-i. Spe-i was first described by McLaughlin et al., Ј who mapped this gene location to a position just 5 of the spe-h TCR V␤ analysis gene (39). Here, we report the cloning and expression of the spe-i ␤ and spe-j genes and the functional analysis of their recombinant V enrichment analysis was performed by anchored multiprimer amplifi- cation (16). Human PBLs were incubated with 20 pg/ml of recombinant proteins. toxin at 106 cells/ml for 3 days. A 2-fold volume expansion of the culture followed with medium containing 20 ng/ml IL-2. After another 24 h, stim- ulated and resting cells were harvested, and RNA was prepared using Materials and Methods Trizol reagent (Life Technologies). A 500 bp ␤-chain DNA probe was Identification of SPE-I and SPE-J obtained by anchored multiprimer PCR, radiolabeled, and hybridized to individual V␤s, and a C␤ DNA region was dot blotted on a nylon mem- SPE-I and SPE-J were identified by searching the S. pyogenes M1 genome brane. The membrane was analyzed on a Molecular Dynamics (Sunnyvale, database at the University of Oklahoma (http://www.genome.ou.edu/ CA) Storm Phosphor imager using ImageQuant software.
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