Human dendritic cells conditioned with Staphylococcus aureus enterotoxin B promote TH2 cell polarization

doi:10.1016/j.jaci.2005.12.1360

Journal of Allergy and Clinical Immunology

Volume 117, Issue 5, May 2006, Pages 1141-1147

https://doi.org/10.1016/j.jaci.2005.12.1360 Get rights and content

Background

Immune surveillance against microbes at sites of interface with environment involves immediate recognition of pathogen-associated molecular patterns by dendritic cells (DCs). According to their first-line position, DCs are key parameters for the establishment of an appropriate innate and adaptive response against pathogens to avoid disease development. Even though their role in pathogenesis is well known, bacterial toxins have been less examined for their ability to drive DC activation and T-cell polarization.

Objective

We made the assumption that early conditioning of DCs with Staphylococcus aureus enterotoxins could take part in T-cell polarization.

Methods

Human monocyte-derived DCs were stimulated with S aureus enterotoxin B (SEB) and characterized with respect to secretion of inflammatory cytokines and their ability to drive polarization of naive allogenic T cells.

Results

We demonstrated that SEB induced maturation of DCs and that SEB-activated DCs secreted high levels of IL-2 but no IL-12p70, contrary to LPS-activated ones. Accordingly, we further showed that SEB-activated DCs were able to drive polarization of naive T cells into the T_H2 subset. By using highly purified SEB and Toll-like receptor (TLR)–2 stably transfected Human Embryonic Kidney (HEK) 293 cells, we demonstrated for the first time the ability of SEB to induce TLR2 signaling. Furthermore, the involvement of SEB-TLR2 interaction in activation of dendritic cells was supported by neutralizing activity of anti-TLR2 antibodies.

Conclusion

Altogether, our findings reinforce the notion that bacterial toxins may appear as new pathogen-associated molecular patterns, which could play a major role in inflammation and bacterial pathologies.

Section snippets

Generation of monocyte-derived DCs

Immature dendritic cells (iDCs) were prepared from PBMCs cultured with GM-CSF (Leucomax; Schering-Plough, Brinny, Ireland) and IL-4 (R&D Systems, Abingdon, United Kingdom).⁷ Phenotype of iDCs was determined as described below. As assessed by flow cytometry using an anti-CD3 antibody, contamination of iDC with T cells ranged between 0.1% and 1%.

Analysis of DC phenotype

Dendritic cells were washed with PBS 5% FCS 0.5 mmol/L EDTA and incubated with conjugated mAbs: fluorescein isothiocyanate (FITC)–anti-CD1a (clone BL6),

SEB induces maturation of human monocyte-derived DCs

To assess the effect of SEB on iDCs, cells were cultured with increasing concentrations of toxin or LPS and analyzed for surface expression of CD83 and CD86, both markers of iDC maturation. Concentrations of SEB (100 ng/mL) and LPS (20 ng/mL) that induced maturation of DCs at a similar magnitude were used. Fig 1, A, shows that, similar to LPS, SEB was able to induce maturation of DCs as determined by upregulation of CD86 and induction of CD83 expression even if later than with LPS. Cytometric

Discussion

There is increasing evidence that colonization of skin and mucosa with microbes play a crucial role in the pathogenesis of T_H cell polarization-dependent diseases. Activation of the inflammatory/innate response is not pathogen-specific but depends on interactions between PAMPs and receptors on DCs such as TLRs. Besides direct interaction of the pathogen with DCs, we can make the assumption that toxins produced by bacteria could be possible triggering factors in the inflammatory process because

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However, the direct effects of SEC2 on APCs were not reported. Previous studies of SEs such as SEA and SEB showed that they could upregulate the expression of factors which were related to Toll-like receptors (TLRs) signaling in DCs [13,14]. The stimulation of TLRs and MyD88 could induced the activation of T cells through NFκB pathway.
As a kind of superantigen, staphylococcal enterotoxin C2 (SEC2) is well known as a powerful immunomodulator. However, most previous studies about SEC2 focus on its T cell activating characters. But the direct effect of SEC2 on antigen-presenting cells (APCs) which are important for the T cell activation is not clearly. In this study, we investigated the effect of SEC2 on murine bone marrow-derived dendritic cells (BMDCs) which are known as the specialized professional APCs. Contrary to its effects on T cells, SEC2 could not induce proliferation or cytotoxicity to BMDCs even in high concentrations. While SEC2 could promote the mature of BMDCs with increased expression of co-stimulatory molecules on cell membrane such as CD80, CD86, and MHC II. The production of pro-inflammatory cytokines such as TNF-α, IFN-γ and IL-6 were also increased in BMDCs treated with SEC2. We also found that SEC2 enhanced the genes expression of pattern recognition receptors including toll-like receptors 2 (TLR2) and TLR4 in BMDCs, and up-regulated the key signal molecule MyD88 in both mRNA and protein levels. In addition, SEC2 also caused IκBα degradating and NFκB p65 translocating from the cytoplasm to the nucleus in BMDCs. The siRNAs for both TLR2 and TLR4, as well as NFκB specific inhibitor BAY 11–7085 could inhibit the co-stimulatory molecules expression and pro-inflammatory cytokines releasing induced by SEC2. Moreover, TLR2/4 specific siRNAs inhibited p65 and MyD88 upregulation induced by SEC2. In summary, all our results indicated that SEC2 could stimulate BMDCs maturation through TLR-NFκB signaling pathways.
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Supported by CERPER-Pierre Fabre (Toulouse) and institutional grants from the Institut National de la Santé et de la Recherche Médicale.

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

View full text

Basic and clinical immunologyHuman dendritic cells conditioned with Staphylococcus aureus enterotoxin B promote TH2 cell polarization

Background

Objective

Methods

Results

Conclusion

Section snippets

Generation of monocyte-derived DCs

Analysis of DC phenotype

SEB induces maturation of human monocyte-derived DCs

Discussion

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Immunol Immunopathol

Trends Microbiol

J Biol Chem

J Allergy Clin Immunol

Dendritic-cell control of pathogen-driven T-cell polarization

Nat Rev Immunol

Toll-like receptors critical proteins linking innate and acquired immunity

Nat Immunol

Interleukin-12 and the regulation of innate resistance and adaptative immunity

Nat Rev Immunol

Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity

EMBO J

Cross-presentation of human cytomegalovirus pp65 (UL83) to CD8+ T cells is regulated by virus-induced, soluble-mediator-dependent maturation of dendritic cells

J Virol

Basic and clinical immunology
Human dendritic cells conditioned with Staphylococcus aureus enterotoxin B promote T_H2 cell polarization