Journal
JOURNAL OF IMMUNOLOGY
Volume 188, Issue 9, Pages 4644-4653Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100272
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Funding
- Juvenile Diabetes Research Foundation U.K. Centre for Diabetes Genes, Autoimmunity, and Prevention [4-2007-1003]
- Juvenile Diabetes Research Foundation International, Wellcome Trust [WT061858]
- National Institute for Health Research Cambridge Biomedical Research Centre
- National Institute for Health Research Biomedical Research Centre at Guy's
- St. Thomas' National Health Service Foundation Trust and King's College London
- Medical Research Council Cusrow Wadia Fund
- European Union [FP7/2007-2013, 241447]
- Diabetes U.K. Ph.D. studentship
- Wellcome Trust [079895]
- Cambridge BioResource Scientific Advisory Board
- management committee
- National Institute for Health Research Cambridge Biomedical Research Center
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10275] Funding Source: researchfish
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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. The Journal of Immunology, 2012, 188: 4644-4653.
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