MHC Class II SAgs show preference for the HLA-DQ form of the molecule. Binding to the α-chain puts the SAg in the appropriate position to coordinate to the TCR. Less commonly, SAgs attach to the polymorphic MHC class II β-chain in an interaction mediated by a zinc ion coordination complex between three SAg residues and a highly conserved region of the HLA-DR β chain. The use of a zinc ion in binding leads to a higher affinity interaction. Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains. This mechanism stimulates cytokine expression and release in antigen presenting cells as well as inducing the production of costimulatory molecules that allow the cell to bind to and activate T cells more effectively. T-cell receptor T-cell binding region of the SAg interacts with the Variable region on the Beta chain of the T-cell Receptor. A given SAg can activate a large proportion of the T-cell population because the human T-cell repertoire comprises only about 50 types of Vβ elements and some SAgs are capable of binding to multiple types of Vβ regions. This interaction varies slightly among the different groups of SAgs. Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more strongly to certain SAgs. Group I SAgs contact the Vβ at the CDR2 and framework region of the molecule. SAgs of Group II interact with the Vβ region using mechanisms that are conformation-dependent. These interactions are for the most part independent of specific Vβ amino acid side-chains. Group IV SAgs have been shown to engage all three CDR loops of certain Vβ forms. The interaction takes place in a cleft between the small and large domains of the SAg and allows the SAg to act as a wedge between the TCR and MHC. This displaces the antigenic peptide away from the TCR and circumvents the normal mechanism for T-cell activation. The biological strength of the SAg (its ability to stimulate) is determined by its affinity for the TCR. SAgs with the highest affinity for the TCR elicit the strongest response. SPMEZ-2 is the most potent SAg discovered to date. T-cell signaling The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the proliferation of the cell and production of cytokines. This occurs because a cognate antigen activates a