Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

Abstract

Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by Staphylococcus aureus and other select staphylococcal species. SAgs function to cross-link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) to stimulate the uncontrolled activation of T lymphocytes, potentially leading to severe human illnesses such as toxic shock syndrome. The ubiquity of SAgs in clinical S. aureus isolates suggests that they likely make an important contribution to the evolutionary fitness of S. aureus. Although the apparent redundancy of SAgs in S. aureus has not been explained, the high level of sequence diversity within this toxin family may allow for SAgs to recognize an assorted range of TCR and MHC class II molecules, as well as aid in the avoidance of humoral immunity. Herein, we outline the major diseases associated with the staphylococcal SAgs and how a dysregulated immune system may contribute to pathology. We then highlight recent research that considers the importance of SAgs in the pathogenesis of S. aureus infections, demonstrating that SAgs are more than simply an immunological diversion. We suggest that SAgs can act as targeted modulators that drive the immune response away from an effective response, and thus aid in S. aureus persistence.

Regulation of toxic shock syndrome toxin‐1 by the accessory gene regulator in Staphylococcus aureus is mediated by the repressor of toxins

“…The staphylococcal superantigens (SAgs) are a family of at least 26 distinct proteins encoded by S. aureus and other select staphylococcal species (Tuffs et al , ). These exotoxins function to cross‐link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) (Li et al , ), and severe intoxication by SAgs can result in the systemic and uncontrolled activation of T cells, leading to a subsequent cytokine storm disease known as the toxic shock syndrome (TSS) (McCormick et al , ; Spaulding et al , ).…”

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

“…However, S. aureus has to produce SAgs for the SAg‐induced direct activation of T cells. Direct treatment of SAgs in mouse or human blood cells could not clearly demonstrate how whole bacteria produced SAgs and promoted V β T cells . Moreover, it cannot be ruled out that the DCs contributed to the V β T‐cell activation .…”

“…Direct treatment of SAgs in mouse or human blood cells could not clearly demonstrate how whole bacteria produced SAgs and promoted Vb T cells. 27,28 Moreover, it cannot be ruled out that the DCs contributed to the Vb T-cell activation. 27 In this study, the mice were inoculated with S. aureus, not SAg, and we found activation of Vb T cells.…”

“…27,28 Moreover, it cannot be ruled out that the DCs contributed to the Vb T-cell activation. 27 In this study, the mice were inoculated with S. aureus, not SAg, and we found activation of Vb T cells. It is not clear whether the S. aureus produces SAgs in the mouse in vivo; however the CD8a À cDCs contributed to induce Vb T-cell activation.…”

Allergy—A New Role for T Cell Superantigens of Staphylococcus aureus?

“…A SAg initially binds to the APC's MHC-II αand/or β-chain outside the antigen presentation site and subsequently cross-links it to the TCR on the T cell. In this process, the SAg binds primarily to the TCR's variable region of the β-chain (Vβ-domain) (or Vα in the case of SEH) [6,32,89]. Each SAg can attach to a characteristic subset of these Vβ elements, which defines its Vβ signature [90].…”