Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells

• Type of Material: Article
• Authors: Lindsay J. Edwards, Emory University; Brian Evavold, Emory University
• Language: English
• Date: 2013-08-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaut.2013.07.002
• Title of Journal or Parent Work: Journal of Autoimmunity
• ISSN: 0896-8411
• Volume: 44
• Start Page: 82
• End Page: 90
• Grant/Funding Information: Funding provided by American Diabetes Association grant 1-09-IN-16 and NIH grant R01 NS062358 (to B.D.E.).
• Keywords: NOD MOUSE; T cell anergy; ANCHOR-SUBSTITUTED VARIANT; NONOBESE DIABETIC MICE; INDUCTION; ACTIVATION; PROTEIN-TYROSINE-PHOSPHATASE; Signaling; CLASS-II MOLECULES; Life Sciences & Biomedicine; ANTIGEN; Type 1 diabetes; I-A(g7); Immunology; Science & Technology; IN-VITRO; RECEPTOR
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

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.