The Journal of Experimental Medicine
StemCell Technologies
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Published 7 June 2004. doi:10.1084/jem.20040139
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1455-1465
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*Diabetes Type 1
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In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes

Qizhi Tang1, Kammi J. Henriksen1, Mingying Bi1, Erik B. Finger1, Greg Szot1, Jianqin Ye1, Emma L. Masteller1, Hugh McDevitt2, Mark Bonyhadi3, and Jeffrey A. Bluestone1

1 UCSF Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, CA 94143
2 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305
3 Xcyte Therapies, Inc., Seattle, WA 98104

Address correspondence to Jeffrey A. Bluestone, UCSF Diabetes Center, University of California San Francisco, Box 0540, 513 Parnassus Avenue, San Francisco, CA 94143. Phone: (415) 514-1683; Fax: (415) 564-5813; email: jbluest{at}diabetes.ucsf.edu

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.

Key Words: autoimmunity • tolerance • CD4+CD25+ T cells • NOD mice • immunoregulation

Abbreviations used in this paper: APC, allophycocyanin; CFSE, carboxyfluorescein diacetate succinimidyl ester; Ct, threshold cycle(s); GITR, glucocorticoid-induced TNF receptor; GAD, glutamic acid decarboxylase; NOD, nonobese diabetic; T1D, type 1 diabetes; Teff, T effector cell; Tg, transgenic; Treg, regulatory T cell.


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