Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
Certain changes in TCR contact residues have been shown to have profound effects on the capacity of a peptide Ag to stimulate a T cell response. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial agonist activity (e.g., cytokine production without proliferation) or antagonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was associated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation of low molecular mass TCRzeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those previously described for partial agonists. Thus, a partial agonist phenotype such as anergy induction cannot be ascribed in a causal manner to this pattern of tyrosine phosphorylation. We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCRzeta isoforms and differential phosphorylation of p120 proto-oncogene c-Cbl. Another early event following TCR engagement by Ag, down-modulation of the TCR, was studied with antagonist peptides. We show that antagonist peptides do not cause TCR down-modulation. This failure may represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.
La Face
D M
DM
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Couture
C
C
Anderson
K
K
Shih
G
G
Alexander
J
J
Sette
A
A
Mustelin
T
T
Altman
A
A
Grey
H M
HM
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases