T cell receptor antagonism mediated by interaction between T cell receptor junctional residues and peptide antigen analogues.
A major objective of new rational immunosuppressive therapies is to be able to inhibit deleterious T cell responses in an Ag-specific manner. Recently, a novel approach to inducing Ag-specific nonresponsiveness in T cells, termed receptor or TCR antagonism, has been described. Several analogues of the influenza hemagglutinin (H3) peptide HA307-319 were shown to block recognition of the native HA307-319 peptide by a DR1-restricted T cell clone at concentrations 1,000- to 10,000-fold less than required to competitively inhibit HA307-319 binding to DR1. These Ag analogues that inhibited T cell recognition differed from the stimulatory antigenic peptide only at single positions. How such limited changes affect the ternary complex interactions of TCR, peptide, and DR remains unclear. In the present study, we have utilized two different DR5-restricted T cell clones that exhibit mutually exclusive specificities for HA peptides with or without substitutions at position 313 to investigate the molecular requirements for receptor antagonism. In this reciprocal model system, we show that a single peptide/DR complex can antagonize one T cell clone while stimulating another. A comparison of nucleotide sequences derived from the TCR of the T cell clones that were either antagonized or stimulated by the peptide analogue/DR5 complex indicated that the different responses of these T cells result from minor differences in the amino acid residues in junctional regions that most likely interact directly with position 313 of the peptide analogues. Our results suggest that TCR antagonism is an Ag-specific phenomenon in which T cells are inhibited by interactions involving TCR residues required for the recognition of conventional Ag and the altered residues in peptide analogues.
Ostrov
D
D
Department of Biological Structure, University of Washington School of Medicine, Seattle 98195.
Krieger
J
J
Sidney
J
J
Sette
A
A
Concannon
P
P
D000595:Amino Acid Sequence; D001483:Base Sequence; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
D006684:HLA-DR Antigens; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta