Unique T cell antagonist properties of the exact self-correlate of a peptide antigen revealed by self-substitution of non-self-positions in the peptide sequence.
The role of self-peptides in shaping the T cell receptor (TCR) repertoire remains to be established. While TCR reactive to certain self-peptides are thought to be depleted in the thymus, the selection of TCR specificity for foreign peptide reactivity appears to require recognition of self-peptide(s) bound to the groove of thymic major histocompatibility complex (MHC) molecules. This dichotomy suggests that different TCR affinities, accessory signals, and/or different sets of self-peptides dictate the eventual fate of any given TCR-bearing clone. Recently, it has been established for several T cell epitopes that derivatives with substitutions in TCR-contact residues can antagonize the proliferation of T cell clones against the wild-type peptide antigen. Moreover, these altered peptide ligands have demonstrated activity in the positive selection of thymocytes with TCR reactive to the wild-type peptide antigen. We have investigated the specificity of T cell antagonism with step-wise substitution of self-amino acids into each nonconserved position of a 12-amino-acid foreign peptide antigen. Our data demonstrate that the ability to antagonize proliferation without competition for MHC binding is unique to the exact self-derivative, where all five of the self-substitutions are inserted. These properties may specifically allow certain self-peptides to downregulate T cell activation to the foreign ligand and/or provide a source of stimulation for immunologic memory.
Schountz
T
T
Division of Biology and the Center for Basic Cancer Research, Kansas State University, Manhattan, 66506, USA.
Kasselman
J P
JP
Ford
S R
SR
Murray
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D017637:Clonal Deletion; D003094:Collagen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D013045:Species Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001324:Autoantigens; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D008024:Ligands; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003094:Collagen