Differential CD3 zeta phosphorylation is not required for the induction of T cell antagonism by altered peptide ligands.
T cells recognize foreign Ags in the form of short peptides bound to MHC molecules. Ligation of the TCR:CD3 complex gives rise to the generation of two tyrosine-phosphorylated forms of the CD3 zeta-chain, pp21 and pp23. Replacement of residues in MHC-bound peptides that alter its recognition by the TCR can generate altered peptide ligands (APL) that antagonize T cell responses to the original agonist peptide, leading to altered T cell function and anergy. This biological process has been linked to differential CD3zeta phosphorylation and generation of only the pp21 phospho-species. Here, we show that T cells expressing CD3zeta mutants, which cannot be phosphorylated, exhibit a 5-fold reduction in IL-2 production and a 30-fold reduction in sensitivity following stimulation with an agonist peptide. However, these T cells are still strongly antagonized by APL. These data demonstrate that: 1) the threshold required for an APL to block a response is much lower than for an agonist peptide to induce a response, 2) CD3zeta is required for full agonist but not antagonist responses, and 3) differential CD3zeta phosphorylation is not a prerequisite for T cell antagonism.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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D000818:Animals; D017951:Antigen Presentation; D017635:Clonal Anergy / Q000276:immunology*; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D006825:Hybridomas; D007376:Interleukin-2 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014162:Transfection / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D007376:Interleukin-2; D008024:Ligands; D008565:Membrane Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine