Diabetogenic CD4 T Cell Recognition of Hybrid Peptide Ligands

混合肽配体的致糖尿病 CD4 T 细胞识别

• 批准号: 10247154
• 负责人: SHAODONG DAI
• 金额: $ 51.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247154
• 关键词: Affinity; Amino Acids; Antigens; Area; Aromatic Amino Acids; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Automobile Driving; Beta Cell; Binding; Biophysics; C-Peptide; C-terminal; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Chromogranin A; Clone Cells; Common Epitope; Complex; Data; Development; Disease; Docking; Epitopes; Goals; Hemorrhage; Human; Human Characteristics; Hybrids; Hyperglycemia; Immune response; Immunotherapy; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Length; Ligands; MHC Class I Genes; MHC Class II Genes; Mammalian Cell; Mediating; Modification; Molecular; Monoclonal Antibodies; Mus; Mutation; N-terminal; Pancreas; Pathogenicity; Pathway interactions; Peptides; Play; Proteins; RNA Splicing; Receptor Activation; Research; Role; Shapes; Specificity; Spottings; Structure; Structure of beta Cell of islet; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell diversity; Testing; Therapeutic; Thymus Gland; Tissues; Variant; autoreactivity; blood glucose regulation; cross reactivity; diabetogenic; granule cell; immunoengineering; in vivo; islet; multicatalytic endopeptidase complex; neoantigens; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; prevent; prototype; receptor binding; transpeptidation

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to understand how diabetogenic T cell receptors (TCRs) recognize the MHCII and hybrid peptide complexes. Peptide ligands of CD4 and CD8 T cells are conventionally derived from contiguous fragments of the parental proteins by the endocytic pathway and proteasome. We first suggested insulin (Ins) B:9-23 and WE14, a natural cleavage product of chromogranin A (ChgA), peptides may be spliced with other beta cell granule proteins and form neo-antigens. We also demonstrated that fusion peptides are the true ligands for many diabetogenic T cells. Both C-terminal modification of the Ins B:9-23 peptide and N- terminal additions to the WE14 peptide of ChgA can create superagonists for T cells. We proposed peptide fusion by transpeptidation as a means of creating the required modifications to the peptides and explain how the T cells driving autoimmunity escape negative selection in the thymus but find their antigen in the target tissue. Our structural and biophysical data showed that the EALYLV portion of Ins B:9-23 and WXRM(D/E) portion of WE14 may be common acceptors of these hybrid peptides. We determined the structures of two different types of mouse TCRs and a human TCR, bound to their optimal versions of the MHCII-Ins peptide ligands. All the Ins reactive TCRs engage the N-terminal portion (EALYL) of Ins B:9-23, indicating similarities in how these ligands are formed in both human and mouse. The structures showed that the specificity differences among mouse Type A and Type B T cells lies in how they interact with the amino acid at p8 (B:21) of the Ins peptide. The structures also show how the peptide modifications were essential to the formation of the complexes, bolstering a role for modification of the peptide in vivo to initiate the CD4 T cell response in T1D. We hypothesize that EALYLV and WXRM(D/E) are the acceptors of the fusion peptides and form the common diabetogenic TCR docking spots, in addition to being novel targets for T1D immunotherapy. Previously, we have shown aromatic amino acids play important role in TCR cross-reactivity. The aromatic amino acids (Y and W) may be the common epitopes for diabetogenic TCRs and critical to shape the broadness of hybrid peptide reactive T cell repertories. Whereas, the donor peptides of hybrid peptides contribute to diversity the T cell repertoire to both Ins and ChgA autoantigens. We will study the following specific aims: Determine how diabetogenic CD4 TCRs recognize IAg7 and ChgA WE14 hybrid peptides; Define the nature of the human Ins B:9-23 hybrid peptides presented to the diabetogenic CD4 TCRs; Test monoclonal antibodies (mAbs) specific for the acceptor portions of the hybrid peptides bound to MHC in the development of T1D. These data may guide therapeutic strategies towards specific modulation of TCR activation, which could be the basis for a novel therapeutic approach in treatment of T1D. Research Strategy Page 2

项目总结/文摘