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
; 60(8): 2125-33, 2011 Aug.
Article
em En
| MEDLINE
| ID: mdl-21715555
ABSTRACT
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 ANDMETHODS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T CD4-Positivos
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Fator de Necrose Tumoral alfa
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Linfócitos T Reguladores
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Interleucina-17
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Diabetes Mellitus Tipo 1
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Fatores de Transcrição Forkhead
Tipo de estudo:
Observational_studies
/
Prognostic_studies
Limite:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article