A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists.
T lymphocyte activation is mediated by the interaction of specific TCR with antigenic peptides bound to MHC molecules. Single amino acid substitutions are often capable of changing the effect of a peptide from stimulatory to antagonistic. Using surface plasmon resonance, we have analyzed the interaction between a complex consisting of variants of the MCC peptide bound to a mouse class II MHC (Ek) and a specific TCR. Using both an improved direct binding method as well as a novel inhibition assay, we show that the affinities of three different antagonist peptide-Ek complexes are approximately 10-50 times lower than that of the wildtype MCC-Ek complex for the TCR, largely due to an increased off-rate. These results suggest that the biological effects of peptide antagonists and partial agonists may be largely based on kinetic parameters.
Lyons
D S
DS
Department of Microbiology and Immunology, Stanford University School of Medicine, California 94305-5402, USA.
Lieberman
S A
SA
Hampl
J
J
Boniface
J J
JJ
Chien
Y
Y
Berg
L J
LJ
Davis
M M
MM
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D003545:Cysteine / Q000737:chemistry; D003574:Cytochrome c Group / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
D003574:Cytochrome c Group; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D003545:Cysteine