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.

Keywords: Cytokine; Staphylococcal Enterotoxin; Staphylococcus aureus; Superantigen; T cell; Toxic Shock Syndrome Toxin-1.

Figure 1

SAgs are two-domain proteins that activate T cell proliferation by binding in an unprocessed form to MHC class II and the TCR. (a) Ribbon cartoon showing the secondary structure of representative staphylococcal superantigens (SAgs). Examples represent each of the 4 major phylogenetic groups; Group I—TSST-1 (PDB: 4OHJ), Group II—SEB (PDB: 3SEB), Group III—SEA (PDB: 1SXT) and Group V—SElK (PDB: 2NTS). The colour defines the two-domain organisation of these proteins the N-terminal OB-fold shaded blue and the C-terminal β-grasp motif shaded red. (b) Conventional antigen presentation and specific T-cell activation results from antigen presenting cell (APC) presenting a processed antigen peptide on the MHC class II molecule which in turn is presented to a specific T-cell receptor (TCR). SAgs crosslink the MHC class II and TCR, unprocessed, and induce uncontrolled activation of T-cells. The SAg binds to the MHC class II outside the antigen presentation site and the variable beta (Vβ) chain of the T-cell receptor. The example interaction given here occurs between MHC class II α-chain and the low affinity site of the SAg (Cell illustrations are from Smart Servier medical art; https://smart.servier.com).

Figure 2

Schematic diagram showing the different cell types targeted by SAgs and the results of cellular activation. Blue arrows indicate direct mechanisms such as binding directly to cells resulting in activation. Green arrows indicate cytokine release or cytokine-mediated cellular activation. Red arrows indicate inhibitory or suppressive mechanisms (Cell illustrations are from Smart Servier medical art; https://smart.servier.com). IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; MyD88: Myeloid differentiation primary response 88; CXCl: Chemokine (C-X-C motif) ligand; CCl: C-C motif chemokine ligand; PMN: polymorphonuclear leukocytes (granulocyte); MAIT; mucosa-associated invariant T cell; iNKT: invariant natural killer T cell.