Marwaha A K, Panagiotopoulos C, Biggs C M, Staiger S, Del Bel K L, Hirschfeld A F, Priatel J J, Turvey S E, Tan R
Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.
Department of Pediatrics, University of British Columbia and Endocrine and Diabetes Unit, British Columbia Children's Hospital, Vancouver, BC, Canada.
Genes Immun. 2017 Jan;18(1):15-21. doi: 10.1038/gene.2016.44. Epub 2017 Jan 5.
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 FOXP3 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 FOXP3IL-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 FOXP3IL-17 cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.
调节性T细胞（Tregs）对免疫耐受至关重要，动物研究表明其功能障碍与1型糖尿病（T1D）的发病机制有关。Tregs的抑制功能需要白细胞介素-2（IL-2），IL-2/IL-2R通路基因的变异与T1D相关。我们之前报道，新发病的T1D患者中分泌促炎细胞因子白细胞介素-17（IL-17）的FOXP3调节性T细胞数量增加。我们假设，IL-2信号缺陷可能通过使保护性调节性T细胞偏向炎症性Th17表型来驱动T1D的发展。总体而言，我们发现，与健康对照相比，T1D患者在诊断前FOXP3+IL-17细胞的比例没有变化。然而，根据IL2RA单核苷酸多态性进行分层显示，携带rs3118470 CC风险变异的T1D患者的调节性T细胞存在IL-2信号缺陷，且在诊断前FOXP3+IL-17细胞的比例增加。这些数据提示了T1D中通过功能失调的IL-2信号导致调节性T细胞功能遗传控制丧失的潜在机制。
