The Journal of Experimental Medicine
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Published 19 August 2002. doi:10.1084/jem.20011845
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© Rockefeller University Press, 0022-1007/2002/8/481/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 481-492
CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

Kristin V. Tarbell1, Mark Lee2, Erik Ranheim2, Cheng Chi Chao2, Maija Sanna2, Seon-Kyeong Kim2, Peter Dickie3, Luc Teyton4, Mark Davis2 and Hugh McDevitt2

1 Program in Immunology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
2 Department of Microbiology and Immunology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
3 Department of Medical Microbiology and Immunology, 1-40 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2
4 Scripps Research Institute, Department of Immunology, La Jolla, CA 92037

Address correspondence to Hugh McDevitt, Dept. of Microbiology and Immunology, Fairchild D-345, Stanford, CA 94305-5124. Phone: 650-723-5893; Fax: 650-723-9180; E-mail: hughmcd{at}stanford.edu

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon {gamma}, interleukin (IL)-2, tumor necrosis factor (TNF)-{alpha}, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

Key Words: T lymphocytes, regulatory • autoimmunity • mouse, NOD • IL-10 • CD152


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