T cells to a dominant epitope of GAD65 express a public CDR3 motif.
Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes, and serve as a model for type 1 diabetes (T1D) and natural autoimmunity. T cell responses to the pancreatic islet antigen glutamic acid decarboxylase 65 (GAD65) can be detected in the spleens of young prediabetic NOD mice, which display a unique MHC class II molecule. Here, we report that a distinct TcR beta chain and CDR3 motif are utilized by all NOD mice in response to a dominant determinant on GAD65, establishing a public repertoire in the spontaneous autoimmunity to an important islet cell antigen. GAD65 530-543 (p530)-reactive T cells preferentially utilize the Vbeta4, Dbeta2.1 and Jbeta2.7 gene segments, with a CDR3 that is characterized by a triad of amino acids, DWG, preceded by a polar residue. In addition, we used CDR3 length spectratyping, CDR3-specific reverse transcriptase-PCR and direct TcR sequencing to show that the TcR beta chain structural patterns associated with p530-specific T cells consistently appeared in the islets of young NOD mice with insulitis, but not in the inflamed islets of streptozotocin-treated C57BL/6 mice, or in inflamed NOD salivary glands. To our knowledge, this is the first report to demonstrate that a public T cell repertoire is used in spontaneous autoimmunity to a dominant self-determinant. These findings suggest that defined clonotypes and repertoires may be preferentially selected in haplotypes predisposed to spontaneous autoimmunity.
Quinn
Anthony
A
Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA. aquinn@utnet.utoledo.edu
McInerney
Marcia
M
Huffman
Donald
D
McInerney
Brigid
B
Mayo
Stella
S
Haskins
Kathryn
K
Sercarz
Eli
E
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007527:Isoenzymes / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D007527:Isoenzymes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2