Up-regulation of IL-17-immunity has been reported in peripheral blood in human type 1 diabetes (T1D). In recent studies, plasticity between regulatory T cells (Tregs), IL-17-producing CD4+ T cells (Th17 cells) and interferon-gamma producing CD4+ T cells (Th1 cells) has been associated with autoimmune diabetes. Our aim was to study IL-17-immunity and plasticity of Th17 cells in the pathogenesis of human T1D.
Our study included 28 children with at least one autoantibody (AAb+), nine children with advanced persistent beta-cell autoimmunity and impaired glucose tolerance (OGTT-children), 81 children without beta-cell autoantibodies (AAb-) and 15 children with newly diagnosed T1D. Plasticity of Th17 cells was studied in AAb(+) -children (n=8), OGTT-children (n=7), AAb(-) -children (n=8) and children with newly onset T1D (n=14). Gene expression levels of Th17-(IL-17A, IL-22, IL-9 and RORC2), Th1-(interferon-gamma), and Treg-(FOXP3) related genes were analyzed with RT-qPCR from anti-CD3+anti-CD-28 stimulated peripheral blood mononuclear cells (PBMCs). To assess Th17 cell plasticity we analyzed gene expression of Th17-(IL-17, IL-17F and IL-9), Th1-(interferon-gamma), and Treg-(FOXP3 and Helios) related genes in FACS-sorted Th17 cells.
Up-regulation of IL-17A/F and IL-22 was seen in patients with T1D. Children with advanced beta-cell autoimmunity showed significantly higher expression of interferon-gamma and IL-9 in stimulated PBMCs in comparison to children with early beta-cell autoimmunity and autoantibody negative children. No differences were seen between the children with early beta-cell autoimmunity and autoantibody negative children in stimulated PBMCs. Sorted IL-17(+) cells expressed high levels of interferon-gamma in children with advanced beta-cell autoimmunity, but no increase was observed in the expression of FOXP3 or Helios.
In conclusion, we demonstrate that up-regulation of interferon-gamma, IL-9 and IL-17 and plasticity of Th17 cells are seen only in the late phase of diabetes development. Our data does not support the hypothesis that Th17 cells would originate from Tregs in patients with beta-cell autoimmunity or T1D.