Uncoupling of Proliferation and Cytokines From Suppression Within the CD4+CD25+Foxp3+ T–Cell Compartment in the 1st Year of Human Type 1 Diabetes
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1661/-/DC1.
- Received November 30, 2010.
- Accepted May 17, 2011.
- © 2011 by the American Diabetes Association.
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