Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events.
T-cell receptor (TCR) antagonism induced by complexes of antigen analogue with major histocompatibility complex (MHC) molecules results in efficient inhibition of antigen-dependent T-cell responses. We have investigated some of the possible mechanisms by which TCR antagonists bound to the MHC molecules of antigen-presenting cells (APCs) can inhibit T-cell activation. Using a nonstimulatory analogue of the antigenic peptide influenza hemagglutinin-(307-319), we showed that MHC/antagonist complexes completely inhibit very early intracellular events of antigen-dependent T-cell activation, such as inositol phosphate turnover and Ca2+ influx. In a parallel series of experiments, the effect of TCR antagonist peptide on membrane-related activation events was also investigated. It was found that MHC/antagonist complexes on the surface of APCs did not induce stable conjugates with T cells and, most interestingly, did not inhibit antigen-induced conjugate formation. Thus, our data suggest that antagonistic peptides do not interfere with the cellular events that are required for stable T-cell/APC conjugate formation but do inhibit early biochemical events required for T-cell proliferation. The data are discussed with respect to the role of surface receptor clustering in TCR antagonism.
Ruppert
J
J
Cytel, San Diego, CA 92121.
Alexander
J
J
Snoke
K
K
Coggeshall
M
M
Herbert
E
E
McKenzie
D
D
Grey
H M
HM
Sette
A
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000276:immunology; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D009975:Orthomyxoviridae / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D007295:Inositol Phosphates; D010455:Peptides; D010743:Phospholipids; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D002118:Calcium