Germline TRAV5D-4 T-cell receptor sequence targets a primary insulin peptide of NOD mice.

Abstract

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.

• Authors: Maki Nakayama, Todd Castoe, Tomasz Sosinowski, XiangLing He, Kelly Johnson, Kathryn Haskins, Dario A A Vignali, Laurent Gapin, David Pollock, George S Eisenbarth
• Journal: Diabetes (Diabetes) Vol. 61 Issue 4 Pg. 857-65 (Apr 2012) ISSN: 1939-327X [Electronic] United States
• PMID: 22315318 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Complementarity Determining Regions
• Insulin
• Peptide Fragments
• Receptors, Antigen, T-Cell, alpha-beta
• insulin B (9-23)

Topics

• Animals
• Autoimmunity
• Complementarity Determining Regions (genetics, metabolism)
• Diabetes Mellitus, Type 1 (genetics)
• Gene Expression Regulation (physiology)
• Germ-Line Mutation
• Insulin (genetics, immunology, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Peptide Fragments (genetics, immunology, metabolism)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, metabolism)
• T-Cell Antigen Receptor Specificity (genetics)
• Time Factors