Tuning peptide specifities for T cell tolerance in Type 1 diabetes

调整 1 型糖尿病 T 细胞耐受性的肽特异性

• 批准号: 10503923
• 负责人: Mark S Anderson
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503923
• 关键词: Ablation; Address; Adoptive Transfer; Affect; Affinity; Agonist; Amino Acids; Antibodies; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacterial Artificial Chromosomes; Binding; Biochemical Pathway; Blood Glucose; CD4 Positive T Lymphocytes; Cells; Characteristics; Clonal Deletion; Collaborations; Coupling; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease Outcome; Epitopes; Future; Generations; Genes; Histocompatibility Antigens Class II; Immune Tolerance; Immunotherapy; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Knock-in; Knowledge; Laboratories; Lead; MHC Class II Genes; Mediating; Modeling; Mus; Mutation; Pathogenicity; Peptide/MHC Complex; Peptides; Peripheral; Positioning Attribute; Prevention; Regulatory T-Lymphocyte; Role; Specificity; T-Cell Immunologic Specificity; T-Lymphocyte; T-cell receptor repertoire; TNFSF11 gene; Testing; Therapeutic; Therapeutic Intervention; Thymus Gland; Time; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translations; Variant; Work; anergy; autoreactive T cell; autoreactivity; central tolerance; diabetes pathogenesis; effector T cell; experience; experimental study; genetic association; genome wide association study; immunoregulation; improved; insight; insulitis; invariant chain; mouse model; novel; peripheral tolerance; prevent; promoter; single cell sequencing; thymus transplantation; tool

Project Summary/Abstract Type 1 Diabetes (T1D) is a classical T-cell mediated autoimmune disease and substantial data implicates insulin as a dominant autoantigen in T1D disease. In the NOD mouse model of T1D, notable studies have shown that mice lacking native insulin expression, but with an altered insulin sequence to maintain blood glucose levels, are completely protected from insulitis and diabetes. Growing evidence also indicates that insulin peptide binding and orientation within MHC Class II (peptide register) is important in determining the strength of interaction and recognition by autoreactive T cells. In collaboration with the Kappler lab, we have uncovered an unusual peptide binding characteristic of the dominant insulin epitope InsB:9-23. The majority of InsB:9-23-specific CD4+ T cells in the periphery recognize insulin bound in this unusual register 3, and by knocking in a single amino acid variation (R to E) into just one copy of the insulin gene in NOD mice (Ins2EE/+), the mice are completely protected against diabetes. The development of a “super agonist” version of the insulin dominant epitopes allows us to address several key questions surrounding the biochemical pathways of peptide generation, presentation by MHC molecules, and recognitions by auto-reactive pathogenic T cells. Do mutations of the major epitope in the insulin gene allow CD4+ T effectors or Treg cells specific for these alternative epitopes to develop? Are mimotopes of these pathogenic epitopes capable of dramatically altering disease outcomes? Are we able to fine tune these epitopes to alter tolerance mechanisms to shift from deletion to Treg induction? Recent work in our lab has focused on the identification of the insulin-specific repertoire on key mouse backgrounds, and we plan to utilize these tools and well-characterized mouse models to examine the effects of altering insulin expression, thymically and extrathymically. These tools as well as our experience with the generation of numerous TCR-transgenic mouse lines will allow us to address these questions in the context of T1D. Thus, we hypothesize that alterations to epitope presentation and TCR affinity drive the tunning of the TCR repertoire towards tolerance and away from self-reactivity. Using Insulin as a model antigen, we propose to test our hypothesis through the following specific aims: Aim 1: Define the role of central tolerance upon the deletion of insulin-reactive clones Aim 2: Characterize the effects of peripheral tolerance on insulin-reactive T cells Aim 3: Explore mechanisms of dominate tolerance to understand the potential for translation into therapeutic treatments for T1D Through these experiments, we hope to gain a nuanced understanding of how changes in insulin epitopes and antigenicity drive the pathogenesis of diabetes and identify targets for future immune modulation and therapeutic intervention for T1D treatment and prevention.

项目总结/文摘