Signal Transduction by Microbial Superantigens via MHC class II Molecules

Chatila, Talal A.; Geha, Raif S.

doi:10.1111/j.1600-065x.1993.tb01529.x

Cited by 56 publications

(32 citation statements)

References 57 publications

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“…Staphylococcal toxic shock syndrome toxin 1 (TSST-1) and the structurally related exotoxins are bacterial exotoxins that bind directly to major histocompatibility complex class II molecules on antigen-presenting cells (1,5,8,18,23) and activate T cells expressing specific V␤ elements (7). These toxins are called superantigens because of their ability to polyclonally stimulate large populations of T cells (1,4,7,14).…”

mentioning

confidence: 99%

Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

Krakauer

Buckley

2003

Antimicrob Agents Chemother

135

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Proinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). Doxycycline inhibited SE-stimulated T-cell proliferation and production of cytokines and chemokines by human peripheral blood mononuclear cells. These results suggest that the antibiotic doxycycline has anti-inflammatory effects and is therapeutically useful for mitigating the pathogenic effects of SE.Staphylococcal toxic shock syndrome toxin 1 (TSST-1) and the structurally related exotoxins are bacterial exotoxins that bind directly to major histocompatibility complex class II molecules on antigen-presenting cells (1,5,8,18,23) and activate T cells expressing specific V␤ elements (7). These toxins are called superantigens because of their ability to polyclonally stimulate large populations of T cells (1,4,7,14). Thus, staphylococcal exotoxins (SE) are potent activators of the immune system and cause a variety of diseases in humans, including food poisoning, toxic shock, and autoimmune diseases (1,2,6,12,14,22). Their interactions with cells of the immune system result in massive production of proinflammatory cytokines and chemokines (1,4,15,17). The cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1 (IL-1), and gamma interferon (IFN-␥) are key mediators in superantigen-induced toxic shock (1, 21). Both TNF-␣ and IL-1 have potent immunostimulating activities and act synergistically with IFN-␥ to enhance immune reactions and promote tissue injury (16). Consequently, these cytokines are pathogenic at high concentrations in vivo and are responsible for fever and toxic shock induced by SE (13,14,18,19).Doxycycline is a broad-spectrum antibiotic widely used for infections caused by both gram-negative and gram-positive microorganisms. It acts as a bacteriostatic agent and is highly effective against many microorganisms, including Staphylococcus aureus, Streptococcus pyogenes, Bacillus anthracis, and Yersinia pestis. Doxycycline belongs to the tetracycline antibiotic family, the members of which have been shown to have other biological actions independent of their antimicrobial effects (10). Doxycycline inhibits phorbol-12-myristate-13-acetate-mediated matrix metalloproteinase 8 (MMP-8) and MMP-9 in human endothelial cells (11). Doxycycline also decreases elastin degradation and reduces MMP activity in a model of aneurismal disease (3). More recently, doxycycline was shown to inhibit the production of IL-1␤ in lipopolysaccharide-treated corneal epithelial cultures to an extent comparable to that achieved by corticosteroids (25). In vivo, doxycycline protected mice from lethal endotoxemia by downregulating cytokine and nitrate secretion in blood (20). This study was undertaken to determine the modulatory effect of doxycycline on staphylococcal superantigen-induced T-cell activation and cytokine production from human peripheral blood mononuclear cells (PBMC).Purified SEB and TSST-1 were obtained from Toxin Technology (Sarasota, Fla.). The endotoxin content of these preparations was Ͻ1 ng of endotoxin/mg of protei...

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mentioning

confidence: 99%

Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

Krakauer

Buckley

2003

Antimicrob Agents Chemother

135

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“…To investigate this and to overcome requirements for specificity, we challenged newly harvested infant thymocytes with superantigen (Sag). Sag binds directly to class II molecules outside the antigen-binding groove and to a variety of Vßs of the TCR, escaping requirements for antigen processing [12]. Our results indicate that significant Sag responses were obtained from suspensions of thymocytes without addition of thymic epithelial cells or macrophages as Sag presenters.…”

Section: Introductionmentioning

confidence: 50%

Superantigens Are Presented by and Activate Thymocytes from Infants

Thulesen

Jørgensen²,

Gerwien³

et al. 1999

Exp Clin Immunogenet

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A high percentage of human fetal and postnatal thymocytes express MHC class II molecules. This raises the possibility that human thymocytes in early life are able to present peptides to other immature T cells and thereby initiate thymic selection of these cells. Here we address this question by exposing newly harvested infant thymocytes to superantigen (Sag) which binds to the T-cell receptor and to MHC class II chains outside the peptide binding groove. The results show that the thymocytes are able to present Sag and to be activated to proliferation as well as apoptosis by Sag presented by other thymocytes. The absence of responses to Sag with mutations in class II binding sites showed that class II molecules were necessary for the responses, and very low expression of class II molecules on CD4–8– cells indicates that the demonstrated T-cell/T-cell interactions are confined to T-cell receptor-positive CD4+8+, CD4+8–, and CD4–8+ cells. These latter subsets were shown to be able to present Sag to each other. These findings suggest that class II+ thymocytes may participate in the selection of self-restricted T cells during a critical period in the shaping of the human immune system.

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“…8, 9, 39, and 40 and reviewed in ref. 41). Exposure to a mixture of SEA and SEB induced a profound inhibition of IL-2-driven growth of human allospecific CD4+ T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Staphylococcal enterotoxins modulate interleukin 2 receptor expression and ligand-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription (Stat proteins).

Nielsen

Svejgaard

Røpke

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Staphylococcal enterotoxins (SE) stimulate T cells expressing the appropriate variable region f3 chain of (V13) T-cell receptors and have been implicated in the pathogenesis of several autoimmune diseases. Depending on costimulatory signals, SE induce either proliferation or anergy in T cells. In addition, SE can induce an interleukin-2 (IL-2) nonresponsive state and apoptosis. Here, we show that SE induce dynamic changes in the expression of and signal transduction through the IL-2 receptor (IL-2R) f3 and y chains (IL-2R13 and IL-2Ry) in human antigen-specific CD4+ T-cell lines. Thus, after 4 hr of exposure to SEA and SEB, the expression of IL-2Rf8 was down-regulated, IL-2Ry was slightly up-regulated, while IL-2Ra remained largely unaffected. The changes in the composition of IL-2Rs were accompanied by inhibition of IL-2-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription called Stat3 and StatS. In parallel experiments, IL-2-driven proliferation was inhibited significantly. After 16 hr of exposure to SE, the expression of IL-2R.3 remained low, while that of IL2Ra and IL2Ry was further up-regulated, and ligand-induced tyrosine phosphorylation of Jak3 and Stat proteins was partly normalized. Yet, IL-2-driven proliferation remained profoundly inhibited, suggesting that signaling events other than Jak3/Stat activation had also been changed following SE stimulation. In conclusion, our data suggest that SE can modulate IL-2R expression and signal transduction involving the Jak/Stat pathway in CD4+ T-cell lines.

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Signal Transduction by Microbial Superantigens via MHC class II Molecules

Cited by 56 publications

References 57 publications

Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

Superantigens Are Presented by and Activate Thymocytes from Infants

Staphylococcal enterotoxins modulate interleukin 2 receptor expression and ligand-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription (Stat proteins).

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