Uptake and Intracellular Trafficking of Superantigens in Dendritic Cells

Abstract

Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II) on the antigen-presenting cell (APC), thereby circumventing intracellular processing to trigger T cell activation. Dendritic cells (DCs) are professional APCs that coat nearly all body surfaces and are the most probable candidate to interact with SAgs. We demonstrate that SAgs are taken up by mouse DCs without triggering DC maturation. SAgs were found in intracellular acidic compartment of DCs as biologically active molecules. Moreover, SAgs co-localized with EEA1, RAB-7 and LAMP-2, at different times, and were then recycled to the cell membrane. DCs loaded with SAgs are capable of triggering in vitro lymphocyte proliferation and, injected into mice, stimulate T cells bearing the proper TCR in draining lymph nodes. Transportation and trafficking of SAgs in DCs might increase the local concentration of these exotoxins where they will produce the highest effect by promoting their encounter with both MHC-II and TCR in lymph nodes, and may explain how just a few SAg molecules can induce the severe pathology associated with TSS.

Regular Exercise Enhances the Immune Response Against Microbial Antigens Through Up-Regulation of Toll-like Receptor Signaling Pathways

“…These data indicate that these antigens induce an enhanced Th1 and pro-inflammatory cytokine response. Antigen presentation by APCs is required for the activation of effector T cells by HBcAg and S. pyogenes [33,34], Previous studies have demonstrated that plasmacytoid DCs are decreased in athletes after running a marathon, and that long-term intensive training may affect the function of innate immune cells, in particular, reducing their capacity to respond to acute challenges, and possibly contributing to an increased risk of infection [35,36]. Moreover, IFN-α and IL-12 derived from DCs play an essential role in Th1 cell differentiation and protecting against pathogen invasion [37].…”

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…Each superantigen is specific for a distinct repertoire of V␤ gene products and can therefore activate up to 20% of circulating naive T cells (358). Rampant T-cell activation has also been shown to occur following the uptake of superantigens by dendritic cells in vivo, further contributing to the proinflammatory cascade (359). In addition, in vitro studies suggest that SpeS can induce a strong proinflammatory response from stratified, squamous epithelial cells (225), suggesting a broader role for superantigens in amplifying the host inflammatory response to GAS.…”

CD8α− conventional dendritic cells control Vβ T‐cell immunity in response to Staphylococcus aureus infection in mice

“…They are the main source for induction of S. aureus ‐mediated cytokine storm; therefore, SAgs can be a target for therapy against S. aureus infection. There are two pathways for immune stimulation by SAgs; direct stimulation of T cells without DCs by SAgs and DC‐contributed activation of T cells by SAgs . Previous studies have shown that SAgs can directly stimulate T cells without antigen presentation processing by DCs, and is mediated by TCR and MHC class II on T cells, which promotes activation of the V β T cells .…”

“…Staphylococcal superantigens (SAgs), the potent immune stimulatory exotoxins, induce T-cell activation and proinflammatory cytokine production by directly cross-linking MHC class II on DCs. 12,13 It has been shown that the DCs are important in the presentation of staphylococcal enterotoxins on MHC class II and secrete interleukin-12 (IL-12) for the induction of T helper type 1 and cytotoxic T1 cells immune responses. 1,[13][14][15] Moreover, the depletion of DCs in mice impaired immunity against S. aureus infection.…”