title: Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells.
abstract: Autoreactive T cells are responsible for inducing several autoimmune diseases, including type 1 diabetes. We have developed a strategy to induce unresponsiveness in these cells by destabilizing the peptide:MHC ligand recognized by the T cell receptor. By introducing amino acid substitutions into the immunogenic peptide at residues that bind to the MHC, the half life of the peptide:MHC complex is severely reduced, thereby resulting in abortive T cell activation and anergy. By treating a monoclonal diabetogenic T cell population with an MHC variant peptide, the cells are rendered unresponsive to the wild type ligand, as measured by both proliferation and IL-2 production. Stimulation of T cells with MHC variant peptides results in minimal Erk1/2 phosphorylation or cell division. Variant peptide stimulation effectively initiates a signaling program dominated by sustained tyrosine phosphatase activity, including elevated SHP-1 activity. These negative signaling events result in an anergic phenotype in which the T cells are not competent to signal through the IL-2 receptor, as evidenced by a lack of phospho-Stat5 upregulation and proliferation, despite high expression of the IL-2 receptor. This unique negative signaling profile provides a novel means to shut down the anti-self response.
authors.affiliation: Department of Microbiology and Immunology, Emory University, 1510 Clifton Rd., Atlanta, GA 30322, USA. lindsayjedwards@gmail.com
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Edwards
authors.forename: Brian D
authors.initials: BD
authors.lastname: Evavold
mesh_terms: D000818:Animals; D002455:Cell Division / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D015375:Receptors, Interleukin-2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
keywords: I-A(g7); Signaling; T cell anergy; Type 1 diabetes
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