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

• Authors: Lindsay J. Edwards, Emory University; Brian Evavold, Emory University
• Journal Title: Journal of Autoimmunity
• Volume: Volume 44
• Publisher: Elsevier: 12 months | 2013-08-01, Pages 82-90
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.jaut.2013.07.002
• Subjects: Biology, Microbiology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; T cell anergy; Type 1 diabetes; I-A(g7); Signaling; NONOBESE DIABETIC MICE; PROTEIN-TYROSINE-PHOSPHATASE; ANCHOR-SUBSTITUTED VARIANT; CLASS-II MOLECULES; NOD MOUSE; IN-VITRO; ANTIGEN; INDUCTION; ACTIVATION; RECEPTOR

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.