title: Alterations of peripheral CD4+CD25+Foxp3+ T regulatory cells in mice with STZ-induced diabetes.
abstract: Complications arising from abnormal immune responses are the major causes of mortality and morbidity in diabetic patients. CD4+CD25+T regulatory cells (Tregs) play pivotal roles in controlling immune homeostasis, immunity and tolerance. The effect of hyperglycemia on CD4+CD25+Tregs has not yet been addressed. Here we used streptozotocin (STZ)-induced diabetic mice to study the effects of long-term hyperglycemia on CD4+CD25+Tregs in vivo. Four months after the onset of diabetes, the frequency of CD4+CD25+Foxp3+ T regulatory cells was significantly elevated in the spleen, peripheral blood lymphocytes (PBLs), peripheral lymph nodes (pLNs) and mesenteric LNs (mLNs). CD4+CD25+Tregs obtained from mice with diabetes displayed defective immunosuppressive functions and an activated/memory phenotype. Insulin administration rescued these changes in the CD4+CD25+ Tregs of diabetic mice. The percentage of thymic CD4+CD25+ naturally occurring Tregs (nTregs) and peripheral CD4+Helios+Foxp3+ nTregs were markedly enhanced in diabetic mice, indicating that thymic output contributed to the increased frequency of peripheral CD4+CD25+Tregs in diabetic mice. In an in vitro assay in which Tregs were induced from CD4+CD25- T cells by transforming growth factor (TGF)-β, high glucose enhanced the efficiency of CD4+CD25+Foxp3+ inducible Tregs (iTregs) induction. In addition, CD4+CD25- T cells from diabetic mice were more susceptible to CD4+CD25+Foxp3+ iTreg differentiation than those cells from control mice. These data, together with the enhanced frequency of CD4+Helios-Foxp3+ iTregs in the periphery of mice with diabetes, indicate that enhanced CD4+CD25+Foxp3+ iTreg induction also contributes to a peripheral increase iCD4+CD25+Tregs in diabetic mice. Our data show that hyperglycemia may alter the frequency of CD4+CD25+Foxp3+ Tregs in mice, which may result in late-state immune dysfunction in patients with diabetes.
authors: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beichen Xi Road 1-5, Beijing, China.
authors: Yu
authors: Y
authors: Zhen
authors: Lina
authors: L
authors: Sun
authors: He
authors: H
authors: Liu
authors: Kaizhong
authors: K
authors: Duan
authors: Chun
authors: C
authors: Zeng
authors: Lianjun
authors: L
authors: Zhang
authors: Di
authors: D
authors: Jin
authors: Jianxia
authors: J
authors: Peng
authors: Wenjun
authors: W
authors: Ding
authors: Yong
authors: Y
authors: Zhao
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D000943:Antigens, Differentiation; D007004:Hypoglycemic Agents; D007328:Insulin