Germline TRAV5D-4 T-cell receptor sequence targets a primary insulin peptide of NOD mice.
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.
Barbara Davis Center for Childhood Diabetes, University of ColoradoSchool of Medicine, Aurora, CO, USA. maki.nakayama@ucdenver.edu
Maki
M
Nakayama
Todd
T
Castoe
Tomasz
T
Sosinowski
XiangLing
X
He
Kelly
K
Johnson
Kathryn
K
Haskins
Dario A A
DA
Vignali
Laurent
L
Gapin
David
D
Pollock
George S
GS
Eisenbarth
D000818:Animals; D015551:Autoimmunity; D022801:Complementarity Determining Regions / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D018095:Germ-Line Mutation; D007328:Insulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013997:Time Factors
D022801:Complementarity Determining Regions; D007328:Insulin; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C097877:insulin B (9-23)