Germline TRAV5D-4 T-Cell Receptor Sequence Targets a Primary Insulin Peptide of NOD Mice

  1. George S. Eisenbarth1
  1. 1Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
  2. 2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
  3. 3Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, Colorado
  4. 4Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
  1. Corresponding author: Maki Nakayama, maki.nakayama{at}


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.


  • Received August 11, 2011.
  • Accepted December 24, 2011.

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