Germline TRAV5D-4 T-Cell Receptor Sequence Targets a Primary Insulin Peptide of NOD Mice
| Autor: | Dario A. A. Vignali, Kathryn Haskins, Laurent Gapin, Tomasz Sosinowski, Todd A. Castoe, Maki Nakayama, XiangLing He, George S. Eisenbarth, David D. Pollock, Kelly Johnson |
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| Rok vydání: | 2012 |
| Předmět: |
Time Factors
Receptors Antigen T-Cell alpha-beta Endocrinology Diabetes and Metabolism medicine.medical_treatment Autoimmunity T-Cell Antigen Receptor Specificity Complementarity determining region Nod Biology medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Germline mutation Mice Inbred NOD Internal Medicine medicine Animals Insulin Germ-Line Mutation 030304 developmental biology NOD mice Mice Knockout Genetics 0303 health sciences Mutation T-cell receptor Complementarity Determining Regions Peptide Fragments Cell biology Diabetes Mellitus Type 1 Gene Expression Regulation Immunology and Transplantation 030215 immunology |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db11-1113 |
| Popis: | There is accumulating evidence that autoimmunity to insulin B chain peptide, amino acids 9–23 (insulin B:9–23), is central to development of autoimmune diabetes of the NOD mouse model. We hypothesized that enhanced susceptibility to autoimmune diabetes is the result of targeting of insulin by a T-cell receptor (TCR) sequence commonly encoded in the germline. In this study, we aimed to demonstrate that a particular Vα gene TRAV5D-4 with multiple junction sequences is sufficient to induce anti-islet autoimmunity by studying retrogenic mouse lines expressing α-chains with different Vα TRAV genes. Retrogenic NOD strains expressing Vα TRAV5D-4 α-chains with many different complementarity determining region (CDR) 3 sequences, even those derived from TCRs recognizing islet-irrelevant molecules, developed anti-insulin autoimmunity. Induction of insulin autoantibodies by TRAV5D-4 α-chains was abrogated by the mutation of insulin peptide B:9–23 or that of two amino acid residues in CDR1 and 2 of the TRAV5D-4. TRAV13–1, the human ortholog of murine TRAV5D-4, was also capable of inducing in vivo anti-insulin autoimmunity when combined with different murine CDR3 sequences. Targeting primary autoantigenic peptides by simple germline-encoded TCR motifs may underlie enhanced susceptibility to the development of autoimmune diabetes. |
| Databáze: | OpenAIRE |
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