MHC class II binding

SAgs do not activate T cells in solution, but generally require multivalent presentation on MHC class II" antigen-presenting cells (APCs). SAgs differ from conventional peptide antigens in that they bind as unprocessed proteins with high affinity to MHC class II molecules on APCs. In this way, SAgs are able to subvert the T cell antigen presentation pathway for their own benefit. The binding of SAgs to MHC

class II is promiscuous and allows each SAg to bind to a large number of different MHC class II alleles and isotypes, although with variable affinity. The binding of SAgs to MHC class II generally occurs outside the conventional peptide-binding groove, bur the affinty is to some extent influenced by the nature of bound peptides.

Structural and functional studies have shown that SEA and SEB share a common binding site located in the amino-terminal domain, interacting with the nonpolymorphic a chain of MHC class II. In addition SEA (as well as SED, SE.E and probably SEH) have a second binding site located in the car-boxyl-terminal domain, which is dependent on a zinc ion for interaction with the (3 chain of MHC class II (Figure 1). Biochemical studies of SEA have shown that three amino acids in domain 2, Hisl87, His225 and Asp227, are crucial for zinc coordination and interaction with MHC class II (Figure 1). Structural models suggest that SEA cannot engage the a and (3 binding sites on a single MHC class II molecule and indicate that SEA may cross-link separate MIIC' class II molecules. Cross-linking of MHC class II by SEA induces the expression of inflammatory cytokines in monocytes. SEA mutants or natural SE variants lacking either the MHC class II a or |3 chain binding sites are unable to stimulate monocytes, implicating that cross-linking of separate MHC class II molecules is a biologically important feature allowing the release of inflammatory cytokines.

Recent studies have demonstrated that SAgs tar geted to cell surfaces, by conjugation of the SAg with monoclonal antibodies to cell surface structures, activate some but not all SAg responding T cells in the absencc of MHC class II. Moreover, SAgs arc able to activate T cells in mice lacking MHC class II. This suggests that SAgs may engage TCRs in a functional manner in the complete absence of MHC class II. A direct interaction between SAgs and the TCR is supported by biochemical and structural data implicating a binding affinity in the |xm to mM range. MHC class II molecules are abundantly expressed on all types of APC. It is therefore possible that MHC class II molecules were favored during evolution as a SAg receptor to allow multivalent presentation on a broad variety of APC. In addition, for certain SAg-TCR combinations, MHC class II molecules contribute to create a high avidity due to the intrinsic affinity between MHC and TCR complexes.

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