1. Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells
- Author
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K L Del Bel, Stuart E. Turvey, Catherine M. Biggs, John J. Priatel, Aaron F. Hirschfeld, S Staiger, Ashish Marwaha, Constadina Panagiotopoulos, and Rusung Tan
- Subjects
0301 basic medicine ,Interleukin 2 ,Genotype ,endocrine system diseases ,medicine.medical_treatment ,Immunology ,Population ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Article ,Immune tolerance ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune Tolerance ,Genetics ,medicine ,Humans ,education ,Genetics (clinical) ,education.field_of_study ,Interleukin-17 ,nutritional and metabolic diseases ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,Flow Cytometry ,Prognosis ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Cytokine ,Interleukin-2 ,Th17 Cells ,Interleukin 17 ,Signal transduction ,Biomarkers ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.
- Published
- 2017