Uncoupling of Proliferation and Cytokines From Suppression Within the CD4+CD25+Foxp3+T-Cell Compartment in the 1st Year of Human Type 1 Diabetes

作者：Hughson Angela; Bromberg Irina; Johnson Barbara; Quataert Sally; Jospe Nicholas; Fowell Deborah J^*

来源：Diabetes, 2011, 60(8): 2125-2133.

DOI：10.2337/db10-1661

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-alpha but not gamma-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. Diabetes 60:2125-2133, 2011

• 出版日期2011-8