Mahmoud Mohamed H, Badr Gamal, Badr Badr Mohamed, Kassem Ahmad Usama, Mohamed Mahmoud Shaaban
Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia; Food Science and Nutrition Department, National Research Center, Dokki, Cairo, Egypt.
Laboratory of Immunology & Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt. Electronic address: http://www.aun.edu.eg/
Cell Signal. 2015 Oct;27(10):2110-9. doi: 10.1016/j.cellsig.2015.07.005. Epub 2015 Jul 18.
Type 1 diabetes mellitus (T1D) is associated with increased type 1 interferon (IFN) levels and subsequent severe defects in lymphocyte function, which increase susceptibility to infections. The blockade of type 1 IFN receptor 1 (IFNAR1) in non-obese diabetic mice has been shown to delay T1D onset and decrease T1D incidence by enhancing spleen CD4+ T cells and restoring B cell function. However, the effect of type 1 IFN blockade during T1D on splenic CD8+ T cells has not previously been studied. Therefore, we investigated, for the first time, the effect of IFNAR1 blockade on the survival and architecture of spleen-homing CD8+ T cells in a streptozotocin-induced T1D mouse model. Three groups of mice were examined: a non-diabetic control group; a diabetic group; and a diabetic group treated with an anti-IFNAR1 blocking antibody. We observed that T1D induction was accompanied by a marked destruction of β cells followed by a marked reduction in insulin levels and increased IFN-α and IFN-β levels in the diabetic group. The diabetic mice also exhibited many abnormal changes including an elevation in blood and spleen free radical (reactive oxygen species and nitric oxide) and pro-inflammatory cytokine (IL-6 and TNF-α) levels, a significant decrease in IL-7 levels, and subsequently, a significant decrease in the numbers of spleen-homing CD8+ T cells. This decrease in spleen-homing CD8+ T cells resulted from a marked reduction in the CCL21-mediated entry of CD8+ T cells into the spleen and from increased apoptosis due to a marked reduction in IL-7-mediated STAT5 and AKT phosphorylation. Interestingly, type 1 IFN signaling blockade in diabetic mice significantly restored the numbers of splenic CD8+ T cells by restoring free radical, pro-inflammatory cytokine and IL-7 levels. These effects subsequently rescued splenic CD8+ T cells from apoptosis through a mechanism that was dependent upon CCL21- and IL-7-mediated signaling. Our data suggest that type 1 IFN is an essential mediator of pathogenesis in T1D and that this role results from the negative effect of IFN signaling on the survival of splenic CD8+ T cells.
1型糖尿病（T1D）与1型干扰素（IFN）水平升高及随后淋巴细胞功能的严重缺陷相关，这会增加感染易感性。在非肥胖糖尿病小鼠中，阻断1型干扰素受体1（IFNAR1）已被证明可通过增强脾脏CD4 + T细胞和恢复B细胞功能来延迟T1D发病并降低T1D发病率。然而，此前尚未研究T1D期间1型干扰素阻断对脾脏CD8 + T细胞的影响。因此，我们首次在链脲佐菌素诱导的T1D小鼠模型中研究了IFNAR1阻断对归巢于脾脏的CD8 + T细胞存活和结构的影响。研究了三组小鼠：非糖尿病对照组；糖尿病组；以及用抗IFNAR1阻断抗体治疗的糖尿病组。我们观察到，T1D诱导伴随着β细胞的显著破坏，随后糖尿病组胰岛素水平显著降低，IFN-α和IFN-β水平升高。糖尿病小鼠还表现出许多异常变化，包括血液和脾脏自由基（活性氧和一氧化氮）及促炎细胞因子（IL-6和TNF-α）水平升高，IL-7水平显著降低，随后归巢于脾脏的CD8 + T细胞数量显著减少。归巢于脾脏的CD8 + T细胞数量减少是由于CCL21介导的CD8 + T细胞进入脾脏显著减少以及由于IL-7介导的STAT5和AKT磷酸化显著降低导致的细胞凋亡增加。有趣的是，糖尿病小鼠中的1型干扰素信号阻断通过恢复自由基、促炎细胞因子和IL-7水平，显著恢复了脾脏CD8 + T细胞的数量。这些作用随后通过依赖CCL21和IL-7介导信号的机制使脾脏CD8 + T细胞免于凋亡。我们的数据表明，1型干扰素是T1D发病机制的重要介质，并且这种作用源于干扰素信号对脾脏CD8 + T细胞存活的负面影响。
