Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome.

Marc Jeschke

Marc Jeschke

Marc Jeschke

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The authors clarified in this study that a compound in Gram-positive bacteria (peptidoglycan) can prevent toxic shock induced by bacterial enterotoxins. Peptidoglycan can activate IL-10 production through Toll-like receptor 2 (TLR2) and may prevent T cell activation in a host. This study explains why the incidence of staphylococcal toxic shock syndrome (TSS) is low although staphylococcal infections are more commonly observed in clinics. It suggests the possible use of heat-inactivated Gram-positive bacterial cell wall compounds (peptidoglycans) as a probiotic reagent to treat/prevent staphylococcal TSS. The study also explains the reason why IL-10 administration was effective in TSS superantigen-induced shock in previous studies. I think the clinical implications of this study are great, and the authors are clever to re-visit this unclear question on bacterial infection/host immune response. In this study, the authors re-visited the molecular mechanism suppressing the toxic shock caused by Staphylococcus, which is one of the common hospital-acquired pathogens. Although Staphylococcus is a major source of superantigens, the incidence of staphylococcal TSS is low. Therefore, the authors hypothesized the down-regulation of immune function by some bacterial compounds, which may protect us from hyperactivation of the immune system by bacterial superantigens/enterotoxins. Although staphylococcal enterotoxin E induces intensive T cell activation, including IL-2 production, exposure of T cells to heat-inactivated S. aureus reduced T cell activation. The same effect was also observed with Gram-positive bacteria that do not produce superantigens; therefore, some Gram-positive bacteria-specific compounds (maybe the compounds of the cell wall) may be responsible for the above T cell down-regulation. Among a few compounds, peptidoglycan seems to play a role in the down-regulation of T cells. TLR2 may be involved as such a pathogen-associated molecule, but it is also known that TLR2 cooperates with other TLRs. Then the authors examined several TLR combinations to test which one was likely to trigger T cell down-regulation. TLR2/6 seems to play a role in the down-regulatory effect, although the blocking of TLR2 with anti-TLR2 was enough to prevent the down-regulation of T cells. Because TLR2 is exclusively expressed in antigen-presenting cells (APCs) and monocytes, the authors hypothesized that staphylococcal peptidoglycan may mainly act on APCs. Here, both monocytes and T cells were purified and used for experiments. The authors found that monocytes always respond well, but T cells did not consistently respond to the bacterial compounds. Supporting this idea, TLR2-deficient B cells did not induce the down-regulation of IL-2 after staphylococcal enterotoxin stimulation. TLR signaling is known to induce canonical NF-kB activation. Therefore, the authors tested the involvement of NF-kB signaling. An NF-kB selective inhibitor diminished the effects of staphylococcal peptidoglycan; thus, it is clear that the NF-kB pathway is involved in TLR2-mediated down-regulation of IL-2 production. Next, the authors focused on IL-10 because IL-10 upregulation was observed in the pilot experiment. Production of IL-10 seems to depend on staphylococcal peptidoglycan. Importantly, the blockage of IL-10 or IL-10 receptor significantly reduced the inhibitory effect of peptidoglycan, suggesting that the binding of staphylococcal peptidoglycan to TLR2 on APCs may trigger IL-10 production, which then down-regulates the IL-2 response to superantigens. IL-10 is known to down-regulate the expression of a T cell co-stimulatory molecule (CD86) on APCs. In fact, after prolonged culture, staphylococcal peptidoglycan reduced the number of CD86-high monocytes, and the disappearance of monocytes is likely to induce apoptosis of monocytes. In the last experiment, the effect of staphylococcal peptidoglycan was tested in the TSS model in mice. Treatment with heat-inactivated S. aureus significantly reduced the mortality of the mice.