Structure-function studies of T-cell receptor-superantigen interactions.

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TitleStructure-function studies of T-cell receptor-superantigen interactions.
Publication TypeJournal Article
Year of Publication1998
AuthorsLi, H, Llera, A, Mariuzza, RA
JournalImmunol Rev
Date Published1998 Jun
KeywordsAmino Acid Sequence, Animals, Antigen Presentation, Antigens, Bacterial, Histocompatibility Antigens Class II, Humans, Kinetics, Mice, Molecular Sequence Data, Mutation, Peptides, Protein Conformation, Receptors, Antigen, T-Cell, alpha-beta, Structure-Activity Relationship, Superantigens, T-Lymphocytes

Superantigens (SAGs) are a class of disease-causing and immunostimulatory proteins of bacterial or viral origin that activate T cells by binding to the V beta domain of the T-cell antigen receptor (TCR). The three-dimensional structure of the complex between a TCR beta chain (mouse V beta 8.2-J beta 2.1-C beta 1) and the SAG staphylococcal enterotoxin C3 (SEC3) has been recently determined. The complementarity-determining region 2 (CDR2) of the beta chain and, to lesser extents, CDR1 and hypervariable region 4 (HV4) bind in a cleft between the small and large domains of the SAG. A model of the TCR-SAG-peptide/MHC complex constructed from available crystal structures reveals how the SAG acts as a wedge between the TCR and MHC, thereby displacing the antigenic peptide away from the TCR and circumventing the normal mechanism for T-cell activation by peptide/MHC. To evaluate the actual contribution of individual SAG residues to stabilizing the V beta C beta-SEC3 complex, as well as to investigate the relationship between the affinity of SAGs for TCB and MHC and their ability to activate T cells, we measured the binding of a set of SEC3 mutants to a soluble recombinant TCR beta chain and to the human MHC class II molecule HLA-DR1. We show that there is direct correlation between affinity and ability to stimulate T cells, with SAGs having the highest affinity for the TCR being the most biologically active. We also find that there is an interplay between TCR-SAG and SAG-MHC interactions in determining mitogenic potency, such that a small increase in the affinity of a SAG for MHC can overcome a large decrease in the SAG's affinity for the TCR. Finally, we observe that those SEC3 residues that make the greatest energetic contribution to stabilizing the V beta C beta-SEC3 complex are strictly conserved among enterotoxins reactive with mouse V beta 8.2, thereby explaining why SAGs having other residues at these positions show different V beta-binding specificities.

Alternate JournalImmunol. Rev.
PubMed ID9700510
Grant List36900 / / PHS HHS / United States