Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg17) cells in type 1 diabetes in non-obese diabetic mice

Abstract

1 S. M. B. and E. N. contributed equally to this work. SummaryT helper type 17 (Th17) cells have been shown to be pathogenic in autoimmune diseases; however, their role in type 1 diabetes (T1D) remains inconclusive. We have found that Th17 differentiation of CD4 1 T cells from BDC2Á5 T cell receptor transgenic non-obese diabetic (NOD) mice can be driven by interleukin (IL)-23 1 IL-6 to produce large amounts of IL-22, and these cells induce T1D in young NOD mice upon adoptive transfer. Conversely, polarizing these cells with transforming growth factor (TGF)-b 1 IL-6 led to non-diabetogenic regulatory Th17 (T reg 17) cells that express high levels of aryl hydrocarbon receptor (AhR) and IL-10 but produced much reduced levels of IL-22. The diabetogenic potential of these Th17 subsets was assessed by adoptive transfer studies in young NOD mice and not NOD.severe combined immunodeficient (SCID) mice to prevent possible transdifferentiation of these cells in vivo. Based upon our results, we suggest that both pathogenic Th17 cells and non-pathogenic regulatory T reg 17 cells can be generated from CD4 1 T cells under appropriate polarization conditions. This may explain the contradictory role of Th17 cells in T1D. The IL-17 producing T reg 17 cells offer a novel regulatory T cell population for the modulation of autoimmunity.

IL-17A blockade or deficiency does not affect progressive renal fibrosis following renal ischaemia reperfusion injury in mice

“…Recent findings suggest that in certain conditions, IL‐17 may have anti‐inflammatory actions . In experimental autoimmune uveitis in rats, IL‐17 inhibition was pro‐inflammatory and aggravated inflammation.…”

Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin-22

“…Moreover, Th22 cells are present mainly in skin or anatomical barriers . In addition, AhR is the transcription factor for the polarization of CD4 + T cells into Th22 cells , and we showed previously that polarization of pathogenic Th17 cells by IL‐23 plus IL‐6 down‐regulated AhR expression . Therefore, the cells producing both IL‐22 and IFN‐γ are of Th17 lineage.…”

“…We found that the expression of aryl hydrocarbon receptor (AhR) did not change significantly in these cells. We have shown previously that pathogenic Th17 cells induced by IL-23 1 IL-6 express little AhR [3]. Conversely, the IL-10 level was significantly lower in the diabetic group versus the non-diabetic NOD mice supporting the down-regulation of regulatory T cells (T reg ) upon disease progression (P < 0Á05).…”

“…The finding that IL‐22 levels are elevated in diabetogenic Th17 cells and receptors for IL‐22 are expressed highly in pancreas prompted us to functionally investigate the role of IL‐22 in Th17 cells in the pathogenesis of T1D. For this purpose we used an adoptive transfer model system of IL‐22‐producing activated Th17 cells to elucidate the effect of anti‐IL‐22 monoclonal antibody in disease pathogenesis in NOD mice.…”

“…We have shown that AhR is expressed in Th17 cells that have been differentiated with TGF‐β plus IL‐6, but not in the pathogenic Th17 cells that have been polarized with IL‐23 + IL‐6. These pathogenic Th17 cells expressed much‐reduced levels of AhR . The induction of Th22 cells is regulated by AhR transcription factor .…”