Staphylococcal enterotoxins condition cells of the innate immune system for Toll-like receptor 4 stimulation

Abstract

In this report we examined overlap between superantigen (SAg) and Toll-like receptor 4 (TLR4) stimulation of the innate immune system. Before in vivo stimulation we found that mouse splenic DCs expressed unexpectedly low levels of surface TLR4 compared to macrophages. In response to LPS, TLR4 gene expression in fractionated spleen cells was downregulated. By comparison, surface TLR4 staining with the Sa15-21 mAb showed little downregulation, and the anti-TLR4 MTS510 mAb showed decreased staining, suggesting that LPS was bound to TLR4 at the time points examined. Interestingly, SAg stimulation induced decreased TLR4 staining as measured by the MTS510 mAb, even though the TLR4 gene was not downregulated. Nevertheless, LPS potently induced DCs to produce TNF and IL-12, but SAg did not, even though they efficiently activated DCs. Notwithstanding, in vivo stimulation with staphylococcal enterotoxin SAg conditioned the innate immune system to hyper-respond to various pathogen-associated molecular patterns (PAMPs). Specifically, pre-priming with SAg enhanced LPS-mediated DC synthesis of TNF and IL-12. Thus, SAgs may exert their pathogenesis on the host by conditioning DCs, in a T cell activation dependent manner to potentiate responses to PAMPs.

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

“…As BLP is the most abundant cell wall component in both Gram-positive and Gram-negative bacteria, this novel finding may explain the mechanisms behind massive proinflammatory cytokine release in sepsis caused by superantigensecreting bacteria (28). Superantigens have been shown to upregulate the expression of both TLR2 and TLR4 on isolated human monocytes (6,7,26), which was also observed in the current study (data not shown). Although this upregulation by superantigen of TLRs may play a role in the increased responsiveness of the innate immune system in superantigen-mediated septic shock, other research has shown that in patients with severe sepsis, TLR expression does not correlate well with ligand sensitivity (31,32).…”

“…This makes them capable of activating up to 20% of the T cell repertoire in an uncontrolled manner (4). Recently, however, superantigens have been shown to activate the innate immune system independently of T cells (6,7,26,27) through direct binding of superantigens to MHC class II receptors on monocytes.…”

Understanding How Lipopolysaccharide Impacts CD4 T-Cell Immunity

“…52,53 This data complements that from adoptive transfer models in which CD28 is required for LPS to enhance CD4 T cell clonal expansion. 90 The greater dependency of peptide-stimulated CD4 T cells on CD28 signaling may result from an ability of superantigens to activate APCs better than peptides, 91,92 or to deliver stronger TCR signals to both CD4 and CD8 T cells.…”

Effects of the physico-chemical nature of two biomimetic crystals on the innate immune response

“…2a depicts the forward (size) and side (granularity) scatter dot plot of PBS treated PECs harvested at 24 h. Because we were interested in activated cells such as macrophages which have high side scatter as we have observed before [24], the R2 and R3 gates were selected as shown in Fig. 2a.…”