The Journal of Experimental Medicine
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Published 7 June 2004. doi:10.1084/jem.20040180
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1467-1477
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*Diabetes Type 1
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CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes

Kristin V. Tarbell, Sayuri Yamazaki, Kara Olson, Priscilla Toy, and Ralph M. Steinman

Laboratory of Cellular Physiology and Immunology, and the Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021

Address correspondence to Ralph M. Steinman, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, Box 176, New York, NY 10021. Phone: (212) 327-8106; Fax: (212) 327-8875; email: steinma{at}mail.rockefeller.edu

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet ß cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 105 polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

Key Words: insulin-dependent diabetes mellitus • dendritic cells • CD25+ CD4+ regulatory • T cells • BDC2.5 • autoimmunity

Abbreviations used in this paper: CFSE, carboxyfluorescein diacetate succinimidyl ester; GITR, glucocorticoid-induced TNF receptor; NOD, nonobese diabetic.


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