title: Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion.
abstract: In nonobese diabetic (NOD) mice, two sets of autoreactive CD4(+) T cells recognize the B:9-23 segment of the insulin B chain. One set, type A, recognizes insulin presented by antigen-presenting cells (APCs). These T cells are highly deleted in the thymus. The second set, type B, does not recognize insulin protein but reacts with soluble B chain peptide. This set is not deleted in the thymus but is activated in the islets of Langerhans. In this study, we examine the specificity of these two types of T cells. The protein-reactive set recognizes the stretch of residues 13-21 of the insulin B chain. The set reactive to peptide only recognizes the stretch from residues 12-20. A single amino acid shift of the B chain peptide bound to I-A(g7) determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging. Biochemical experiments indicate that peptides bound in the 13-21 register interact more favorably with I-A(g7) than peptides that bind in the 12-20 register. Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in registers distinct from those found in the thymus.
authors: Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors: James F
authors: JF
authors: Mohan
authors: Shirley J
authors: SJ
authors: Petzold
authors: Emil R
authors: ER
authors: Unanue
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D007328:Insulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D011485:Protein Binding; D037182:T-Cell Antigen Receptor Specificity; D013950:Thymus Gland / Q000276:immunology
chemical_list: D017931:DNA Primers; D007328:Insulin