Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice.
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 beta 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 5x10(4) 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.
Tarbell
Kristin V
KV
Laboratory of Cellular Physiology and Immunology and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021, USA. tarbelk@rockefeller.edu
Petit
Lucine
L
Zuo
Xiaopan
X
Toy
Priscilla
P
Luo
Xunrong
X
Mqadmi
Amina
A
Yang
Hua
H
Suthanthiran
Manikkam
M
Mojsov
Svetlana
S
Steinman
Ralph M
RM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology*; D019041:L-Selectin / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000097:blood / Q000276:immunology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin