Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3 + IL-17 + cells

Genes Immun. 2017 Jan;18(1):15-21. doi: 10.1038/gene.2016.44. Epub 2017 Jan 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / metabolism
  • Diabetes Mellitus, Type 1 / diagnosis*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics*
  • Genotype
  • Humans
  • Immune Tolerance
  • Interleukin-17 / genetics*
  • Interleukin-2 / genetics*
  • Prognosis
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells

Substances

  • Biomarkers
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL17A protein, human
  • Interleukin-17
  • Interleukin-2