Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes

Diabetes. 2008 Jan;57(1):113-23. doi: 10.2337/db06-1700. Epub 2007 Oct 10.


Objective: In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp3(+)CD4(+) regulatory T-cells (nT(reg)), which display potent inhibitory effects on T-cell functions in vitro and in vivo, may predispose to the development of type 1 diabetes.

Research design and methods: We assessed the frequency and function of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues in the NOD animal model of type 1 diabetes.

Results: We show that the cellular frequency of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues is stable and does not decline relative to type 1 diabetes-resistant mice. We show that thymic and peripheral CD4(+)CD25(+) T-cells are fully functional in vivo. We also examined the functional impact of CD4(+)Foxp3(+) nT(reg) cells on the development of autoimmune diabetes, and we demonstrate that nT(reg) cells do not affect the initial priming or expansion of antigen-specific diabetogenic T-cells but impact their differentiation in pancreatic lymph nodes. Moreover, CD4(+)Foxp3(+) nT(reg) cells also regulate later events of diabetogenesis by preferentially localizing in the pancreatic environment where they suppress the accumulation and function of effector T-cells. Finally, we show that the nT(reg) cell functional potency and intra-pancreatic proliferative potential declines with age, in turn augmenting diabetogenic responses and disease susceptibility.

Conclusions: This study demonstrates that Foxp3-expressing nT(reg) cells in NOD mice regulate diabetogenesis, but temporal alterations in nT(reg) cell function promote immune dysregulation and the onset of spontaneous autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Division
  • Cytokines / immunology
  • Cytokines / physiology
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology
  • Islets of Langerhans
  • Ki-67 Antigen / physiology
  • Lymphocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Pancreas / pathology
  • Phenotype
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Ki-67 Antigen