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International Immunology Advance Access published online on April 26, 2006
International Immunology, doi:10.1093/intimm/dxl033
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 17, 2005
Accepted March 24, 2006

Article

T cells to a dominant epitope of GAD65 express a public CDR3 motif

Anthony Quinn 1 *, Marcia McInerney 2, Donald Huffman 3, Brigid McInerney 3, Stella Mayo 1, Kathryn Haskins 4, and Eli Sercarz 5

1 Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA
2 Department of Medicinal and Biological Chemistry, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA
3 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
4 Department of Immunology and Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262, USA
5 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA; Present address: Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA

* To whom correspondence should be addressed.
Anthony Quinn, E-mail: aquinn{at}utnet.utoledo.edu


  Abstract

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 V{beta}4, D{beta}2.1 and J{beta}2.7 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.

Keywords: autoimmunity; diabetes; gene rearrangements; NOD; TcR.
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[Abstract] [Full Text] [PDF]


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