Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells.
Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4(+) GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligand-mediated antagonism is inhibited in a dose-dependent manner by the presence of non-antagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.
Gebe
John A
JA
Benaroya Research Institute at Virginia Mason, Seattle, USA. jgebe@benaroyaresearch.org
Masewicz
Susan A
SA
Kochik
Sharon A
SA
Reijonen
Helena
H
Nepom
Gerald T
GT
D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008024:Ligands; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*
D000939:Epitopes; D007376:Interleukin-2; D007527:Isoenzymes; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2