Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function.
J Immunol
; 188(9): 4644-53, 2012 May 01.
Article
en En
| MEDLINE
| ID: mdl-22461703
ABSTRACT
Numerous reports have demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses when compared with nondiseased, control individuals. Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development. Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease. Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined. We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function. Studies were conducted using healthy human subjects to avoid any confounding effects of disease. We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells. These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Polimorfismo Genético
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Transducción de Señal
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Interleucina-2
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Linfocitos T Reguladores
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Diabetes Mellitus Tipo 1
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Subunidad alfa del Receptor de Interleucina-2
Tipo de estudio:
Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
J Immunol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido