Genetic deletion of IL-17 suppresses the progression to diabetes in the NOD mice in the Age-dependent fashion

T辅助类型17(Th17)细胞已被证明在几种以前被认为Th1占优势的自身免疫性疾病的小鼠模型中发挥重要作用。然而，在NOD小鼠中，IL-17/Th17的相关性仍然存在争议，因为它们具有内在的可塑性。来源于BDC2.5 NOD小鼠的Th17细胞在体内通过转化为Th1细胞转移糖尿病。我们研究了IL-17单一缺乏或IL-17/干扰素-γ受体双缺乏对NOD小鼠发生胰岛素炎/糖尿病的影响。IL-17单一缺乏可显著延缓糖尿病的发生并减轻胰岛素炎症的严重程度，但IL-17缺陷小鼠50周龄糖尿病的累积发病率与野生型(Wt)小鼠相似。用年轻的非糖尿病IL-17单一缺陷NOD小鼠的CD4+CD25-T细胞进行的过继转移研究表明，与相应的wt-小鼠相比，受体NOD-SCID小鼠的疾病也显著延迟。另一方面，IL-17/干扰素-γ受体双缺陷显著抑制糖尿病的发展，尽管单缺陷和双缺陷小鼠的胰岛素炎症水平相似。这些结果表明IL-17/Th17在糖尿病前期NOD小鼠胰岛素炎的发生发展中起重要作用，Th1-Th17细胞的相互作用有助于糖尿病的发生。

T helper type 17(Th17) cells have been shown to play important roles in mouse models of several autoimmune diseases that had previously been thought Th1-dominant. In the NOD mouse, however, the relevance of IL-17/Th17 is still controversial, because of their inherent plasticity. Th17 cells derived from BDC2.5 NOD mice transfer diabetes through conversion to Th1 cells in vivo. We here studied the impact of IL-17 single-deficiency or IL-17/IFN-γreceptor double-deficiency on the development of insulitis/diabetes in NOD mice. IL-17 single-deficiency significantly delayed the onset of diabetes and attenuated the severity of insulitis, but the cumulative incidence of diabetes until 50 weeks of age in IL-17 deficient mice was similar to that in wild-type(wt) mice. Adoptive transfer study with CD4+CD25-T cells from young non-diabetic IL-17 single-deficient NOD mice, but not that from older mice showed also significantly delayed disease in the recipient NOD-Scid mice as compared with those from the corresponding wt-mice. On the other hand, IL-17/IFN-γreceptor double-deficiency significantly suppressed the development of diabetes, although the levels of insulitis were similar between single-deficient and double-deficient mice. These results indicate that IL-17/Th17 plays a significant role in the development of insulitis in pre-diabetic NOD mice and the interaction of Th1-Th17 cells contributes to diabetes development.