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At least 19 recordsLinked to original sources
PubMed1997

Microbial superantigens stimulate T cells by the superantigen bridge and independently by a cytokine pathway.

Superantigens cross-link the MHC II molecule on accessory cells with the Vbeta region of the T cell receptor (TCR). In this study, we compared the capacity of established superantigens for inducing cytokine release. The experimental protocol was generated to answer the question whether all superantigen effects are transmitted by the MHC/TCR cross-linkage and induce mainly a T cell response. We found that TSST-1, ExFTA, and SEC3 differed from all other superantigens tested because they stimulated a stronger monokine release. T cell proliferation after challenge with these superantigens was mainly mediated by a cytokine pathway and not by the cross-linkage of MHC and TCR. For the other superantigens, we were able to demonstrate that major immunomodulatory effect is mediated by the superantigen bridge. With the exception of these three superantigens, the proliferative response of superantigens correlated with their Vbeta specificity. Interleukin-1 (IL-1) and IL-6 were induced in monocytes by all superantigens, whereas tumor necrosis factor-alpha (TNF-alpha) was induced in T cells and by some superantigens, also in monocytes. IL-2 was always induced by the superantigen bridge, whereas interferon-gamma (IFN-gamma) was also induced indirectly by monokines. Collectively, our results indicate that not all superantigens are suitable for investigating superantigen-specific effects, as they show indirect (mitogenic) side effects. Observations for an individual superantigen are, therefore, not transferable to all other superantigens.

Antigens, Bacterial↗
PubMed2004

Broad-spectrum immunity against superantigens is elicited in mice protected from lethal shock by a superantigen antagonist peptide.

Bypassing the restricted presentation of conventional antigens, superantigens trigger an excessive cellular immune response leading to toxic shock. Antagonist peptides that inhibit the induction of human Th1 cytokine gene expression by a variety of bacterial superantigens protect mice from lethal toxic shock. We show that the surviving mice rapidly develop a broad-spectrum, protective immunity against further lethal toxin challenges with the same superantigen and even with superantigen toxins that they have not encountered before. By blocking the induction of a cellular immune response leading to toxic shock, the antagonist peptide allows the superantigen to induce a vigorous humoral immune response directed against itself, resulting in anti-toxin IgM and IgG that are broadly protective. Adoptive transfer of these antibodies to naïve mice rendered them resistant to lethal superantigen challenge. The appearance of these antibodies does not require immunization with an adjuvant and is not elicited by the antagonist peptide. Our results show that superantigens are potent immunogens when given the opportunity to induce a B cell response, in conditions where a deleterious Th1 response is prevented by the superantigen antagonist peptide.

Adoptive Transfer↗
PubMed2005

Persistence of zinc-binding bacterial superantigens at the surface of antigen-presenting cells contributes to the extreme potency of these superantigens as T-cell activators.

Bacterial superantigen intoxication causes massive overactivation of T cells, which can result in potentially lethal toxic shock. Superantigens fall into two groups: superantigens such as staphylococcal enterotoxin B (SEB) that contain a single generic binding site for major histocompatibility complex class II (MHC-II) and more potent superantigens such as SEA with a second, zinc-dependent MHC-II binding site that enables them to cross-link adjacent MHC-II molecules. We found that although all superantigens bound rapidly to the surface of human B cells, zinc-binding superantigens largely remained at the cell surface for at least 40 h. In contrast, single-binding-site superantigens were greatly depleted from the surface by 4 h. Subcellular fractionation and confocal microscopy revealed that some SEB entered lysosomal compartments, but SEA remained almost undetectable inside cells at 20 h. SEA and SEB mutants that do not bind MHC-II were trafficked rapidly to lysosomal compartments. Our findings suggest that the persistence of SEA and other zinc-dependent, cross-linking superantigens on the surface of antigen-presenting cells contributes to their potency as T-cell activators.

Antigen-Presenting Cells↗
PubMed1993

Interaction between T cells and murine acquired immunodeficiency virus superantigen: effect of second signal on T cell reactivity to the MAIDS virus superantigen.

A murine acquired immunodeficiency (MAIDS) virus transformed B cell line, B6-1710, was shown to express superantigen activity and stimulate T cell hybridomas to produce IL-2. However, T cell clones and lines from which B6-1710 reactive hybridomas were established failed to proliferate upon stimulation with B6-1710, while B6-1710 cells were capable of presenting bacterial superantigen to stimulate both T cell hybridomas and clones. Proliferative response of T cells to MAIDS virus superantigen could be detected by the addition of the pharmacological agent phorbol myristate acetate (PMA). Thus, B6-1710 seems to lack a stimulatory activity necessary for the proliferative response of T cells to the MAIDS viral superantigen. In the analysis of the response of naive splenic T cells to the MAIDS superantigen, T cells recovered from a culture stimulated with B6-1710 cells in the presence of PMA showed no dominant TCR V beta chain usage, while cells recovered from a culture stimulated with B6-1710 alone were dominated by T cells expressing V beta 5, 11, and 12 TCR chains. These results suggest that T cells bearing a majority of TCR V beta chains are capable of responding to B6-1710 superantigen. The avidity of interaction between T cells and viral superantigen may differ significantly among T cells and those T cells exhibiting weak interaction with MAIDS virus superantigen may require additional signals, such as PMA, for an in vitro proliferative response to B6-1710 cells.

Animals↗
PubMed1995

Type I interferon inhibition of superantigen stimulation: implications for treatment of superantigen-associated disease.

The interferons (IFNs) are a family of secretory glycoproteins possessing potent antiviral, antiproliferative, antimicrobial, and immunomodulatory activities. It has been shown that the IFNs and superantigens have an important effect on the course of certain autoimmune disorders, and thus we have examined the effect of the type I and type II IFNs on superantigen-induced stimulation. The type I IFNs, alpha, beta, and tau, inhibited induction of T cell proliferation by several staphylococcal enterotoxin superantigens; the type II IFN, gamma, was without effect. The type I IFNs inhibited T cell proliferation to the same extent, approximately 50% at 10(3) units of IFN/ml, and in a dose-dependent manner. Consistent with inhibition of proliferation, the type I IFNs also inhibited IL-2 production as well as levels of IL-2 receptor expression. Inhibition was not increased by using the IFNs in combination, suggesting that they inhibited proliferation by the same mechanism. IFNs alpha and beta, but not IFN-tau, were toxic to cells at high concentrations (> or = 10(4) units/ml). Thus, the mechanism by which type I IFNs inhibit cell proliferation differs from that associated with their toxic effects. A partial reduction of V beta-specific superantigen-induced T cell expansion by type I IFNs was also demonstrated using flow cytometry. We recently showed that superantigens play an important role in the reactivation of experimental allergic encephalomyelitis. The potent antiproliferative activities of the type I IFNs strongly suggest the further study of their use as therapies for superantigen-associated diseases, such as multiple sclerosis and other autoimmune disorders, as well as toxic shock syndrome.

Autoimmune Diseases↗
PubMed1996

A kinetic comparative study on lymphocyte responses to superantigen and phytohemagglutinin: reciprocal presentation of superantigen on the surface of activated lymphocytes.

The kinetics of thymidine incorporation into fractionated T lymphocytes responding to bacterial superantigens were compared to those of cells activated by phytohemagglutinin (PHA). Evident differences between the kinetics of cell proliferation induced by PHA-P and staphylococcal enterotoxin B (SEB) emerged after Day 4 of culture. PHA-P-induced proliferative responses of peripheral blood mononuclear cells (PBMCs) and fractionated cells were apparent on Day 4 because of the presence of accessory cells in the initial cell suspensions. This gradually diminished in correlation with the decline of accessory cells in the cultures. The SEB-induced cell growth (PBMCs and CD4+ cells), however, continued until Day 9 of the culture. This finding suggests the reciprocal usage of MHC class II molecules to present SEB by activated T lymphocytes for superantigen-induced T cell activation and suggests that superantigen-related immune activation may depend in part on the potential of activated T lymphocytes to mediate reciprocal cell-to-cell interactions in the presence of superantigens. The decline observed in the CD8+ cell response to SEB and toxic shock syndrome toxin-1 after Day 4 was revived by exogenous recombinant interleukin-2 (rIL-2) supplementation, suggesting that the consequent autocrine or paracrine secretion of IL-2 from the responding cells is essential for subsequent cell proliferation. SEB-induced cell proliferation was significantly suppressed by anti-CD11a (lymphocyte function-associated antigen-1; LFA-1, alpha-chain) monoclonal antibody, and the inhibitory effect was most obvious in 6-day cultured CD8+ lymphocytes. The results suggest that the lymphocyte response associated with the cell-to-cell copresentation of superantigens involves LFA-1 molecules as an accessory factor, particularly in CD8+ lymphocytes.

Antibodies, Monoclonal↗
PubMed1997

Structural basis for the interaction of superantigen with the alternative superantigen-binding receptor p85.

Superantigens are microbial products which bind both to the TCR beta-chain and, with moderate affinity, to MHC class II molecules. Class II-bearing cells bind the superantigen and present the superantigen to T cells expressing certain TCR beta-chain variable region alleles. We have previously reported that the superantigen staphylococcal enterotoxin B (SEB) binds with moderate affinity to the protein p85 expressed on COS-1, an African Green Monkey kidney fibroblast-like cell line. In the present report we carry out a structural analysis to examine the basis for the interaction of superantigen to p85. We show that SEC1, SEC2, and SEC3 also bind to p85 based on inhibition of the binding of radiolabeled SEB. On the other hand, SEA, SED, SEE and toxic shock syndrome toxin-1 do not exhibit detectable binding. In an effort to characterize the structural basis for the SEB binding to p85, we have generated both amino- and carboxy-terminal truncations of SEB expressed as fusion proteins with the maltose-binding protein of Escherichia coli. Our results show that the full-length SEB fusion protein and a truncation missing the 81 amino-terminal amino acids both compete successfully with native SEB for binding. On the other hand, carboxy-terminal truncations in which 19 or 34 residues are deleted both fail to compete for binding. These results are consistent with results which show that monoclonal anti-SEB antibodies specific for carboxy-terminal determinants block SEB binding to p85, but an amino-terminal mAb fails to exhibit any alteration in binding. These results suggest that residues at or near the carboxy-terminus of SEB play a role in binding to p85.

Amino Acid Sequence↗
PubMed1994

I-J revisited: is the I-J genetic restriction in downregulation due to an endogenous superantigen analogous to mammary tumour virus (Mtv)-encoded endogenous superantigen?

This article puts forward the hypothesis that the I-J genetic restriction observed between certain downregulatory (suppressor) T cells and antigen presenting cells is due to an endogenous superantigen analogous to the mouse mammary tumour virus (Mtv) products encoded by the open reading frames in the 3' long terminal repeat (LTR) of mtv's. In its weak form this hypothesis asserts that the I-J genetic restriction is due to an endogenous superantigen ligand on antigen presenting cells, which crosslinks the V beta and/or V alpha chains of certain T cell receptors (TCR) with major histocompatibility complex (MHC) class II, and that MHC together with this superantigen ligand causes positive selection of T cells bearing the appropriate I-J+ TCR in the thymus. In the periphery these T cells recognize peptide/MHC complex in the presence of the superantigen. In its strong form the hypothesis states that this superantigen ligand for TCR and MHC is encoded by integrated virus genome, e.g. Mtv. These possibilities can now be approached experimentally and their exploration may uncover one of the ways in which T cells are assigned to different functions, including downregulation.

Animals↗
PubMed1998

Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors.

Staphylococcal enterotoxin B is a member of a family of toxins known as superantigens that activate a large number of T-cells (up to 20%) by cross-linking MHC class II molecules with T-cell receptors in a Vbeta-restricted fashion. The crystal structure of staphylococcal enterotoxin B presented here has been determined at 1.5 A resolution, the highest resolution so far for a superantigen. The final model contains 1948 protein atoms and 177 water molecules and has excellent geometry with root-mean-square (rms) deviation of 0.007 A and 1.73 degrees in bond lengths and bond angles, respectively. The overall fold is similar to that of other microbial superantigens, but as it lacks the zinc-binding site found in other members of this family, such as staphylococcal enterotoxin A, C2 and D, this enterotoxin possesses only one MHC class II binding site. Comparison of the crystal structure of free SEB and in complex with an MHC class II molecule revealed no major changes in the MHC-binding site upon complex formation. However, a number of water molecules found in the free SEB may be displaced in the complex or contribute further to its stability. Detailed analysis of the TcR-binding site of SEB, SEA and SEC2 shows significant differences which may account for the ability of each superantigen to bind specific Vbeta sequences.

Amino Acid Sequence↗
PubMedDate not supplied

Hyporesponsiveness of peripheral blood lymphocytes to streptococcal superantigens in patients with guttate psoriasis: evidence for systemic stimulation of T cells with superantigens released from focally infecting Streptococcus pyogenes.

Throat infection with Streptococcus pyogenes is the most important trigger for acute guttate psoriasis. We examined the in vitro responses of peripheral blood mononuclear cells (PBMC) to streptococcal superantigens, SPEA and SPEC, and staphylococcal superantigens, SEB and TSST-1, in patients with guttate psoriasis, in patients with chronic plaque psoriasis, and in healthy subjects. PBMC from patients with guttate psoriasis responded poorly to SPEA and SPEC at concentrations of 0.1 and 1 ng/ml as compared with those from patients with plaque psoriasis, but showed high responses to SEB and TSST-1. The hyporesponsiveness recovered after improvement of the skin eruption. There was no significant difference between guttate and chronic types of psoriasis in the percentage of circulating T-cell receptor BV2 or BV8-bearing T cells, responsive to streptococcal superantigens, indicating that T-cell clonal anergy was a mechanism underlying the hyporesponsiveness. Our results suggest that superantigens released from focally infecting S. pyogenes induce a transient activation of relevant T cells, leading to the development of skin eruption and, subsequently, temporary T-cell anergy to these toxins.

Adult↗
PubMed2002

Superantigen concomitantly induces Th1 cytokine genes and the ability to shut off their expression on re-exposure to superantigen.

Superantigens, exemplified by staphylococcal enterotoxin B (SEB), are the strongest known inducers of a cellular immune response; they elicit the production of excessive amounts of Th1 cytokines, IL-2, IFN-gamma and TNF, leading to toxic shock. We show that increasing doses of SEB cause not only a greater induction but also a more rapid cessation of IL-2 gene expression. Remarkably, exposure of human PBMC to a second dose of SEB, even at concentrations 10- or 100-fold lower than the initial inducing dose and even within 2 h after the first exposure to SEB, resulted in an immediate and essentially complete shutoff of the induced IL-2 and IFN-gamma mRNA expression. The shutoff response was observed when primary induction of IL-2 and IFN-gamma gene expression was by SEB but not when it was by phytohemaggutinin-P. Signaling by a superantigen thus results not only in a vigorous induction of Th1 cytokine genes but concomitantly induces the ability to shut off their expression upon re-exposure to superantigen. Without induction of this negative control mechanism, the cellular immune response to a superantigen would be even more pronounced.

Cells, Cultured↗
PubMed2000

Conservation and variation in superantigen structure and activity highlighted by the three-dimensional structures of two new superantigens from Streptococcus pyogenes.

Bacterial superantigens (SAgs) are a structurally related group of protein toxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They are implicated in a range of human pathologies associated with bacterial infection whose symptoms result from SAg-mediated stimulation of a large number (2-20%) of T-cells. At the molecular level, bacterial SAgs bind to major histocompatability class II (MHC-II) molecules and disrupt the normal interaction between MHC-II and T-cell receptors (TCRs). We have determined high-resolution crystal structures of two newly identified streptococcal superantigens, SPE-H and SMEZ-2. Both structures conform to the generic bacterial superantigen folding pattern, comprising an OB-fold N-terminal domain and a beta-grasp C-terminal domain. SPE-H and SMEZ-2 also display very similar zinc-binding sites on the outer concave surfaces of their C-terminal domains. Structural comparisons with other SAgs identify two structural sub-families. Sub-families are related by conserved core residues and demarcated by variable binding surfaces for MHC-II and TCR. SMEZ-2 is most closely related to the streptococcal SAg SPE-C, and together they constitute one structural sub-family. In contrast, SPE-H appears to be a hybrid whose N-terminal domain is most closely related to the SEB sub-family and whose C-terminal domain is most closely related to the SPE-C/SMEZ-2 sub-family. MHC-II binding for both SPE-H and SMEZ-2 is mediated by the zinc ion at their C-terminal face, whereas the generic N-terminal domain MHC-II binding site found on many SAgs appears not to be present. Structural comparisons provide evidence for variations in TCR binding between SPE-H, SMEZ-2 and other members of the SAg family; the extreme potency of SMEZ-2 (active at 10(-15) g ml-1 levels) is likely to be related to its TCR binding properties. The smez gene shows allelic variation that maps onto a considerable proportion of the protein surface. This allelic variation, coupled with the varied binding modes of SAgs to MHC-II and TCR, highlights the pressure on SAgs to avoid host immune defences.

Alleles↗
PubMed2004

Crystal structure of Mycoplasma arthritidis mitogen complexed with HLA-DR1 reveals a novel superantigen fold and a dimerized superantigen-MHC complex.

Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing particular TCR Vbeta elements. Here we report the crystal structure of MAM complexed with a major histocompatibility complex (MHC) antigen, HLA-DR1, loaded with haemagglutinin peptide 306-318 (HA). The structure reveals that MAM has a novel fold composed of two alpha-helical domains. This fold is entirely different from that of the pyrogenic superantigens, consisting of a beta-grasped motif and a beta barrel. In the complex, the N-terminal domain of MAM binds orthogonally to the MHC alpha1 domain and the bound HA peptide, and to a lesser extent to the MHC beta1 domain. Two MAM molecules form an asymmetric dimer and cross-link two MHC antigens to form a plausible, dimerized MAM-MHC complex. These data provide the first crystallographic evidence that superantigens can dimerize MHC molecules. Based on our structure, a model of the TCR2MAM2MHC2 complex is proposed.

Antigens↗
PubMed2003

Preparation of a superantigen-adsorbing device and its superantigen removal efficacies in vitro and in vivo.

OBJECTIVE: A new superantigen-adsorbing device (SAAD) was developed, and its characteristics and efficacy in septic animals were evaluated. METHODS: The SAAD was prepared by stepwise chemical modification of a polystyrene-based composite fiber reinforced with polypropylene. Adsorption affinities for several factors and the biological effect of superantigen (SAg) removal were measured in vitro. Also, superantigen-infused rabbits were treated with SAAD, and the efficacy was evaluated in vivo. RESULTS: When the SAAD was evaluated for its ability to adsorb SAg in human plasma (1 ng/mL each), the adsorption rates were 74%, 76% and 85% for staphylococcal enterotoxins A, B and C, respectively, and 80% and 72% for toxic shock syndrome toxin-1 (TSST-1) and streptococcal pyrogenic exotoxin A, respectively. In addition, the SAAD showed some affinity towards other molecules, such as streptococcal pyrogenic exotoxin B, beta2-microglobulin, and vancomycin. Residual activities in whole blood samples containing TSST-1 (1 ng/mL) after incubation with the SAAD were 125 pg/mL for tumor necrosis factor alpha (TNF-alpha) production, and 359 pg/mL for interleukin-8 (IL-8) production (the initial activities: 194 pg/mL for TNF-alpha production, and 1029 pg/mL for IL-8 production). When TSST-1/lipopolysaccharide (LPS)-infused rabbits were subjected to extracorporeal blood purification with a SAAD column, 50% of the animals survived for a 14-day period after the infusion. In contrast, all control animals died within 3 days after the infusion. CONCLUSION: These results indicate that the SAg-adsorbing device may be useful in treating SAg-related diseases.

Adsorption↗
PubMed1996

The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of functional domains and comparison with microbial superantigens and plant lectin mitogens.

Mycoplasma arthritidis, an agent of chronic proliferative arthritis of rodents, secretes a potent soluble superantigen, MAM, that is active for both murine and human T and B lymphocytes. We now report the complete nucleotide and amino acid sequence of MAM and show it to be distinct from other proteins and not closely related phylogenetically to other superantigens. Two functional domains on MAM are identified based on the ability of peptides encompassing these regions to inhibit lymphocyte proliferation by the intact MAM molecule. One of these domains shares short sequences or epitopes with other microbial superantigens. The second domain contains the consensus legume lectin motif-beta, which is important for T cell activation by concanavalin (Con) A. MAM and Con A peptides containing this motif are functionally cross reactive, suggesting a novel secondary pathway for T cell activation by MAM.

Amino Acid Sequence↗
PubMed2005

Endogenous superantigens shape response to exogenous superantigens.

Endogenous superantigen-mediated thymic negative selection resulted in a paucity of mature T cells bearing T-cell receptor (TCR) Vbeta8 in the periphery. Consequently, the magnitude of immune response to exogenous superantigen staphylococcal enterotoxin B, which activates TCR Vbeta8(+) T cells, was significantly reduced and conferred protection from superantigen-induced mortality.

Animals↗
PubMed2002

Frequency of superantigen-producing Staphylococcus intermedius isolates from canine pyoderma and proliferation-inducing potential of superantigens in dogs.

This preliminary study investigated the potential role of staphylococcal superantigens in the pathogenesis of canine pyoderma. The staphylococcal enterotoxins A (SEA), SEB, SEC and SED, and the toxic shock syndrome toxin-1 (TSST-1) were assayed in isolates from skins of dogs with pyoderma. Culture supernatants from 25 of 96 isolates were positive for multiple superantigens, with SEA and SEC being the most frequently detected. In in vitro stimulation of canine peripheral blood mononuclear cells and quantitative flow cytometry revealed that low concentrations of SEA and SEB were potent stimulators of blastogenesis of T cells.

Animals↗
PubMed2003

Regulation of mouse mammary tumor virus env transcriptional activator initiated mammary tumor virus superantigen transcripts in lymphomas of SJL/J mice: role of Ikaros, demethylation, and chromatin structural change in the transcriptional activation of mammary tumor virus superantigen.

Mammary tumor virus (Mtv29)-encoded superantigen expressed by SJL/J mouse B cell lymphomas stimulates CD4+V16+ T cells and thereby acquires T cell help necessary for lymphoma growth. Mtv29 mouse mammary tumor virus env transcriptional activator (META) env-controlled Mtv29 superantigen (vSAg29) mRNA transcripts (1.8 kb) are not expressed in normal B or other somatic cells. Real-time PCR-based assays with DNA from normal SJL liver and vSAg29- lymphoma (cNJ101), digested with methylation-sensitive enzymes, showed hypermethylation at AvaI, FspI, HpaII, ThaI, and the distal HgaI sites of the META env, but vSAg29+ lymphoma cells showed significant demethylation at AvaI, HpaII, and the distal HgaI sites. The distal HgaI site that is adjacent to an Ikaros binding site is significantly demethylated in the META env DNA from primary lymphomas. Gel shift assays showed binding of Ikaros to a sequence representing this region in the META env. SJL lymphomas expressed the Ikaros isoform Ik6 that was absent in normal B cells. vSAg29+ cells exhibited increased DNaseI accessibility to chromatin at the vSAg29 initiation site. Treatment of cNJ101 cells with a demethylating agent, 5-azacytidine, and a histone deacetylase inhibitor, trichostatin A, caused hypomethylation at AvaI, HpaII, and distal HgaI sites and led to chromatin structural change at the vSAg29 initiation site, accompanied by the expression of vSAg29 transcripts. This enabled cNJ101 cells to stimulate SJL lymphoma-responsive CD4+V16+ T hybridoma cells. Thus, demethylation at the distal HgaI site of the Mtv29 META env permits vSAg29 expression, which may have an impact on the development of germinal center-derived B cell lymphomas of SJL/J mice.

Animals↗