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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901587v1 183/11/7585    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Li, L. Articles by Tisch, R. PubMed PubMed Citation Articles by Li, L. Articles by Tisch, R.

β Cell-Specific CD4⁺ T Cell Clonotypes in Peripheral Blood and the Pancreatic Islets Are Distinct¹

Li Li,^* Qiuming He,^* Alaina Garland,^* Zuoan Yi,^* Lydia T. Aybar,^* Thomas B. Kepler, Jeffrey A. Frelinger,^* Bo Wang,^* and Roland Tisch^2*

^*Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and Center for Computational Immunology, Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710

Type 1 diabetes is an autoimmune disease mediated by β cell-specific CD4⁺ and CD8⁺ T cells. Tracking β cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral β cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4⁺ T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IA^g7-Ig (sIA^g7-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIA^g7-mBDC) were used to identify or isolate CD4⁺ T cells from PBL and the islets of NOD mice. A temporal increase in sIA^g7-mBDC binding (g7-mBDC⁺) T cells corresponding with the progression of β cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC⁺ T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-β and CDR-β gene usage of single islet-infiltrating g7-mBDC⁺ CD4⁺ T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR β-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC⁺ T cells. These results demonstrate that PBL and islet CD4⁺ T cells specific for a given β cell epitope can differ regarding pathogenicity and TCR repertoire.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01AI058014 from the National Institutes of Health, Grant 7-04-RA-121 from American Diabetes Association (to R.T.), and Grant 1-2008-24 from the Juvenile Diabetes Research Foundation (to J.A.F.). A.G. was supported by training Grant 5T32 AI07273 from the National Institutes of Health. B.W. was supported by Award 1-04-CD-09 from the American Diabetes Association Career Development Program.

² Address correspondence and reprint requests to Dr. Roland Tisch, Department of Microbiology and Immunology, Mary Ellen Jones Building, Room 804, Campus Box No. 7290, University of North Carolina, Chapel Hill, NC 27599-7290. E-mail address: rmtisch{at}med.unc.edu

³ Abbreviations used in this paper: T1D, type 1 diabetes; GAD, glutamic acid decarboxylase; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; TRBV, TCR β-chain variable; mBDC, mimetic BDC.

⁴ The online version of this article contains supplemental material.