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J Biol Chem, Vol. 275, Issue 1, 312-321, January 7, 2000
From the Monovalent major histocompatibility
complex-peptide complexes dissociate within seconds from the T-cell
receptor (TCR), indicating that dimerization/multimerization may be
important during early stages of T-cell activation. Soluble bivalent
HLA-DR2·myelin basic protein (MBP) peptide complexes were expressed
by replacing the F(ab) arms of an IgG2a antibody with HLA-DR2·MBP
peptide complexes. The binding of bivalent HLA-DR2·peptide complexes
to recombinant TCR was examined by surface plasmon resonance. The
bivalent nature greatly enhanced TCR binding and slowed dissociation
from the TCR, with a t1/2 of 2.1 to 4.6 min. Soluble bivalent HLA-DR2·MBP peptide complexes activated
antigen-specific T-cells in the absence of antigen presenting cells. In
contrast, soluble antibodies to the TCR·CD3 complex were ineffective,
indicating that they failed to induce an active TCR dimer. TCR/CD3
antibodies induced T-cell proliferation when bound by antigen
presenting cells that expressed Fc receptors. In the presence of
dendritic cells, bivalent HLA-DR2·MBP peptide complexes induced
T-cell activation at >100-fold lower concentrations than TCR/CD3
antibodies and were also superior to peptide or antigen. These results
demonstrate that bivalent HLA-DR·peptide complexes represent
effective ligands for activation of the TCR. The data support a role
for TCR dimerization in early TCR signaling and kinetic proofreading.
Kinetics of T-cell Receptor Binding by Bivalent HLA-DR·Peptide
Complexes That Activate Antigen-specific Human T-cells*
§¶,§,, and
**
Department of Cancer Immunology & AIDS,
Dana-Farber Cancer Institute and the Department of Neurology,
Harvard Medical School, Boston, Massachusetts 02115
*
This work was supported in part by grants from the National
Multiple Sclerosis Society and the National Institutes of Health (to
K. W. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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