INVESTIGADORES
LLERA Andrea Sabina
artículos
Título:
Structure-function studies of T cell receptor-superantigen interaction
Autor/es:
LI, HM; LLERA ANDREA S; MARIUZZA, RA
Revista:
IMMUNOLOGICAL REVIEWS
Referencias:
Año: 1998 vol. 163 p. 177 - 186
ISSN:
0105-2896
Resumen:
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.