The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20061631
The Journal of Experimental Medicine, Vol. 204, No. 1, 191-201
The Rockefeller University Press, 0022-1007 $30.00
© Tarbell et al.
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ARTICLE

 Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

Kristin V. Tarbell1,2, Lucine Petit1,2, Xiaopan Zuo1,2, Priscilla Toy1,2, Xunrong Luo3, Amina Mqadmi1,2, Hua Yang3, Manikkam Suthanthiran3, Svetlana Mojsov1,2, and Ralph M. Steinman1,2

1 Laboratory of Cellular Physiology and Immunology and 2 Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
3 Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021

CORRESPONDENCE Kristin Tarbell: tarbelk{at}rockefeller.edu

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet ß cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 x 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

Abbreviations used: CFSE, carboxyfluorescein diacetate succinimidyl ester; GLP-1, glucagon-like peptide 1; NOD, nonobese diabetic.

X. Luo's present address is Depts. of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.


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