The Staphylococcus aureus Enterotoxin B Superantigen Induces Specific T Cell Receptor Down-regulation by Increasing Its Internalization

Abstract

Superantigens are able to stimulate T lymphocyte populations expressing T cell antigen receptors (TCR) belonging to particular V beta families. Moreover, the presence of these superantigens may induce long term unresponsiveness (anergy) of these sensitive cells. Some bacterial toxins are potent superantigens. We have analyzed in vitro the capacity of some Staphylococcus aureus enterotoxin superantigens to modulate T cell antigen receptor expression and the cellular mechanisms involved. Staphylococcus enterotoxin B (SEB) induced rapid down-regulation of surface T cell antigen receptors in V beta 3-expressing T lymphocytes, as assessed by flow cytometry. This phenomenon was a consequence of the direct interaction between the toxin and the TCR since it was observed in the absence of cells expressing major histocompatibility complex class II molecules. The cellular mechanism involved in SEB-induced down-regulation of TCR was further investigated. Immunofluorescence and confocal microscopy experiments showed that toxin B induced intracellular accumulation of TCR.CD3 in endocytic vesicles. Moreover, SEB induced an increase in T cell receptor endocytosis as measured using radiolabeled Fab fragments of an anti-CD3 monoclonal antibody. Taken together, our observations indicate that Staphylococcus enterotoxin B superantigen induced changes in the dynamics of surface T cell receptors, which resulted in the fast reduction of membrane receptor numbers.

TCR-Vβ8 as Alternative to Animal Testing for Quantifying Active SEE

“…This finding is not in accordance with the findings of Fleischer and Schrezenmeier [23] and Spertini et al [27], who reported that a T-cell clone could respond directly to SEA and SEB (which are in different class than SEE) in the absence of accessory cells. This finding also contrasts with Niedergang's et al [24], observation of a biological effect of SEB on Vβ3-transfected Jurkat cells in the complete absence of accessory cells. It is worth noting that the fluorescently labeled SEE was able to reduce TCR Vβ8 protein expression and induce expression of the luciferase gene with the same efficiency as unlabeled SEE.…”

“…At 1 ng/mL SEE, measurable cell associated SEE is essentially at background levels. This finding is in contrast to what has been reported by others that did not observe any binding of SEB to T cells [24]. …”

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

“…Conventional T cells are also known to downregulate their TCRs upon exposure to SEB. 54 By contrast, SEBactivated mouse iNKT cells remained detectable at all time points examined. Human iNKT cells also clearly lost their TCR surface expression in response to aGC, but not SEB, which followed a different kinetics in comparison with mouse iNKT cells-that is they were still undetectable at least up until day 7.…”

Constitutive and Ligand-Induced TCR Degradation

“…In theory, TCR down-regulation can be accomplished by an increase in the endocytic rate constant, a decrease in the exocytic rate constant, or a combination of both. Most studies found that TCR down-regulation is caused by an increase in the endocytic rate constant after TCR triggering (13,15,17,28,33); however, some studies indicated that TCR ligation induces TCR down-regulation by a reduction in the exocytic rate constant rather than by an increase in the endocytic rate constant (16). Divergent models for TCR degradation also exist.…”

“…Thus, at steady state a certain amount of TCR is endocytosed, while at the same time an equal amount of TCR is exocytosed. Several studies seem to agree that the constitutive endocytic rate constant for the TCR in resting T cells is ϳ0.01 min Ϫ1 , meaning that 1% of the cell surface-expressed TCR is internalized each minute (11,(15)(16)(17). However, whether the TCR is endocytosed and further processed as an intact receptor or as individual subunits with different endocytic, exocytic, and degradation rate constants remains unclear.…”