Germline TRAV5D-4 T-Cell Receptor Sequence Targets a Primary Insulin Peptide of NOD Mice
- Maki Nakayama1,
- Todd Castoe2,
- Tomasz Sosinowski3,
- XiangLing He1,
- Kelly Johnson1,
- Kathryn Haskins3,
- Dario A.A. Vignali4,
- Laurent Gapin3,
- David Pollock2 and
- George S. Eisenbarth1
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
- 2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
- 3Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, Colorado
- 4Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Corresponding author: Maki Nakayama, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1113/-/DC1.
- Received August 11, 2011.
- Accepted December 24, 2011.
- © 2012 by the American Diabetes Association.
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