Uncoupling of proliferation and cytokines from suppression within the CD4+CD25+Foxp3+ T-cell compartment in the 1st year of human type 1 diabetes

Diabetes. 2011 Aug;60(8):2125-33. doi: 10.2337/db10-1661. Epub 2011 Jun 29.


Objective: The mechanistic basis for the breakdown of T-cell tolerance in type 1 diabetes is unclear and could result from a gain of effector function and/or loss of regulatory function. In humans, the CD4+CD25+Foxp3+ T-cell compartment contains both effector and regulatory T cells, and it is not known how their relative proportions vary in disease states.

Research design and methods: We performed a longitudinal study of CD4+CD25+ T-cell function in children with type 1 diabetes at onset and throughout the 1st year of disease. Function was assessed using single-cell assays of proliferation, cytokine production, and suppression. Type 1 diabetic individuals were compared with age-matched control subjects, and suppression was directly assessed by coculture with control T-cell targets.

Results: We identify novel functional changes within the type 1 diabetes CD4+CD25+ compartment. Type 1 diabetic CD4+CD25+ cells exhibited a striking increase in proliferative capacity in coculture with CD4 T cells that was present at onset and stable 9-12 months from diagnosis. Elevated type 1 diabetes CD4+CD25+ cell proliferation correlated with increased inflammatory cytokines interleukin 17 and tumor necrosis factor-α but not γ-interferon. Type 1 diabetes CD4+CD25+ cytokine production occurred coincident with suppression of the same cytokines in the control targets. Indeed, enhanced proliferation/cytokines by CD4+CD25+ cells was uncoupled from their suppressive ability. Longitudinally, we observed a transient defect in type 1 diabetes CD4+CD25+ suppression that unexpectedly correlated with measures of improved metabolic function.

Conclusions: Type 1 diabetes onset, and its subsequent remission period, is associated with two independent functional changes within the CD4+CD25+ T-cell compartment: a stable increase in effector function and a transient decrease in regulatory T-cell suppression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Child
  • Coculture Techniques
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Immune Tolerance / immunology
  • Interleukin-17 / immunology*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Longitudinal Studies
  • Male
  • Middle Aged
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor-alpha / immunology*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-17
  • Interleukin-2 Receptor alpha Subunit
  • Tumor Necrosis Factor-alpha