J. Exp. Med., Volume 187, Number 6, March 16, 1998 823-833

A Mutational Analysis of the Binding of Staphylococcal Enterotoxins B and C3 to the T Cell Receptor  Chain and Major Histocompatibility Complex Class II

By Lukas Leder,^* Andrea Llera,^* Pascal M. Lavoie, Marina I. Lebedeva,^* Hongmin Li,^* Rafick-Pierre Sékaly, Gregory A. Bohach,^§ Pamala J. Gahr, Patrick M. Schlievert, Klaus Karjalainen,^¶ and Roy A. Mariuzza^*

From the ^* Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850;  Laboratoire d'Immunologie, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada; the ^§ Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, Idaho 83844; the  Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455; and the ^¶ Basel Institute for Immunology, Postfach CH-4005, Basel, Switzerland

The three-dimensional structure of the complex between a T cell receptor (TCR)  chain (mouse V8.2J2.1C1) and the superantigen (SAG) staphylococcal enterotoxin C3 (SEC3) has been recently determined to 3.5 Å resolution. To evaluate the actual contribution of individual SAG residues to stabilizing the -SEC3 complex, as well as to investigate the relationship between the affinity of SAGs for TCR and MHC and their ability to activate T cells, we measured the binding of a set of SEC3 and staphylococcal enterotoxin B (SEB) mutants to soluble recombinant TCR  chain and to the human MHC class II molecule HLA-DR1. Affinities were determined by sedimentation equilibrium and/or surface plasmon detection, while mitogenic potency was assessed using T cells from rearrangement-deficient TCR transgenic mice. We show that there is a clear and simple relationship between the affinity of SAGs for the TCR and their biological activity: the tighter the binding of a particular mutant of SEC3 or SEB to the TCR  chain, the greater its ability to stimulate T cells. 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 -SEC3 complex ("hot spot" residues) are strictly conserved among enterotoxins reactive with mouse V8.2, thereby providing a basis for understanding why SAGs having other residues at these positions show different V-binding specificities.

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