ISSN:
1600-065X
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Summary: Superantigens (SAGs) are a class of disease-causing and immunostimulatory proteins of bacterial or viral origin that activate T cells by binding to the Vβ domain of the T-cell antigen receptor (TCR), The three-dimensional structure of the complex between a TCR β chain (mouse Vβ8.2-Jβ2.l-Cβ1) and the SAG staphylococcal enterotoxin d (SEC3) has been recently determined. The complementarity-determining region 2 (CDR2) of the β 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 die antigen in 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 VβCβ-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 mutants to a soluble recombinant TCR β 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 die 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 die affinity of a SAG for MHC can overcome a large decrease in the SAG's affinity for die TCR, Finally, we observe that those SEC3 residues that make the greatest energetic contribution to stabilizing the VβCβ-SEC3 complex are strictly conserved among enterotoxins reactive with mouse Vβ8.2, thereby explaining why SAGs having other residues at diese positions show different Vβ-binding specificities.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1600-065X.1998.tb01196.x
