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Staphylococcal Enterotoxin D Is a Promiscuous Superantigen Offering Multiple Modes of Interactions With the MHC Class II Receptors¹

Reem Al-Daccak^2,*, Khalil Mehindate^2,*, Farida Damdoumi^*, Pierre Etongué-Mayer^*, Helen Nilsson, Per Antonsson, Michael Sundström, Mikael Dohlsten, Rafick-Pierre Sékaly^§ and Walid Mourad^3,*

^* Centre de Recherche en Rhumatologie Immunologie, Le Centre Hospitalier de l’Université Laval, Sainte-Foy, Quebec, Canada; Pharmacia & Upjohn Research Center, Lund, Sweden; Pharmacia & Upjohn, Stockholm, Sweden; and ^§ Laboratoire d’Immunology, Institut de Recherche Clinique de Montréal, Montreal, Quebec, Canada

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-1ß and TNF- gene expression in these cells. Using mutated toxins that lost their binding site with the MHC class II - or ß-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 -chains (/), ß-chains (ß/ß), or the - and ß-chains of two different class II molecules. The ß/ß 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 ß-chain. The different modes of SED interactions also influence SED-induced T cell activation where simultaneous ligation of the - and ß-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 /ß/peptide complexes.

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