title: Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function.
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.
authors.affiliation: Department of Immunobiology, School of Medicine, King's College London, London SE1 9RT, United Kingdom.
authors.forename: Garima
authors.initials: G
authors.lastname: Garg
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Tyler
authors.forename: Jennie H M
authors.initials: JH
authors.lastname: Yang
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Marcin
authors.initials: M
authors.lastname: Pekalski
authors.forename: Gwynneth L
authors.initials: GL
authors.lastname: Bell
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Timothy I M
authors.initials: TI
authors.lastname: Tree
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins