title: Staphylococcal enterotoxin D is a promiscuous superantigen offering multiple modes of interactions with the MHC class II receptors.
abstract: Dimerization of MHC class II molecules on the cell surface of human THP-1 monocytic cell line is a requirement for staphylococcal superantigen (SAG)-induced cytokine gene expression. The capacities of various SAG to induce this response are governed by their modes of interaction with MHC class II molecules. Staphylococcal enterotoxin A (SEA), with its two binding sites, dimerizes MHC class II molecules and subsequently induces cytokine gene expression in THP-1 cells. Here, we demonstrate that staphylococcal enterotoxin D (SED) and staphylococcal enterotoxin E (SEE) induce, similarly, IL-1beta and TNF-alpha gene expression in these cells. Using mutated toxins that lost their binding site with the MHC class II alpha- or beta-chain, we demonstrate that this response is also mediated by the dimerization of MHC class II molecules through two binding sites. Furthermore, SED forms Zn2+-dependent homodimers that allow multiple modes of MHC class II clustering, including ligation of alpha-chains (alpha/alpha), beta-chains (beta/beta), or the alpha- and beta-chains of two different class II molecules. The beta/beta interaction following Zn2+-dependent SED/SED homodimer formation seems to be mediated by the appearance of a novel binding site on SED that interacts with histidine 81 of the MHC class II beta-chain. The different modes of SED interactions also influence SED-induced T cell activation where simultaneous ligation of the alpha- and beta-chains is essential for optimal response. These various modes of SED binding may be used to preserve bivalency regardless of variability in the MHC class II alpha/beta/peptide complexes.
authors.affiliation: Centre de Recherche en Rhumatologie Immunologie, Le Centre Hospitalier de l'Université Laval, Sainte-Foy, Quebec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Al-Daccak
authors.forename: K
authors.initials: K
authors.lastname: Mehindate
authors.forename: F
authors.initials: F
authors.lastname: Damdoumi
authors.forename: P
authors.initials: P
authors.lastname: Etongué-Mayer
authors.forename: H
authors.initials: H
authors.lastname: Nilsson
authors.forename: P
authors.initials: P
authors.lastname: Antonsson
authors.forename: M
authors.initials: M
authors.lastname: Sundström
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
authors.forename: R P
authors.initials: RP
authors.lastname: Sékaly
authors.forename: W
authors.initials: W
authors.lastname: Mourad
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D019281:Dimerization; D004768:Enterotoxins / Q000276:immunology*; D006681:HLA-D Antigens / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D008213:Lymphocyte Activation; D012333:RNA, Messenger / Q000235:genetics; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015032:Zinc
chemical_list: D004768:Enterotoxins; D006681:HLA-D Antigens; D007375:Interleukin-1; D012333:RNA, Messenger; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C019368:enterotoxin D, Staphylococcal; D015032:Zinc