Elevated IFN-alpha/beta levels in a streptozotocin-induced type I diabetic mouse model promote oxidative stress and mediate depletion of spleen-homing CD8+ T cells by apoptosis through impaired CCL21/CCR7 axis and IL-7/CD127 signaling

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.

Keywords: Apoptosis; CCL21, CD127, CD8+ T cell; Diabetes; Free radicals; IFN-α/β; Spleen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • CD8-Positive T-Lymphocytes / physiology*
  • Chemokine CCL21 / physiology
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Type 1 / blood*
  • Interferon-alpha
  • Interferon-beta / blood
  • Interleukin-7 / physiology
  • Interleukin-7 Receptor alpha Subunit / physiology
  • Membrane Potential, Mitochondrial
  • Mice, Inbred BALB C
  • Oxidative Stress
  • Reactive Oxygen Species
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, CCR7 / physiology
  • Signal Transduction
  • Spleen / immunology*
  • Spleen / pathology
  • Streptozocin


  • Ccr7 protein, mouse
  • Chemokine CCL21
  • Ifnar1 protein, mouse
  • Interferon-alpha
  • Interleukin-7
  • Interleukin-7 Receptor alpha Subunit
  • Reactive Oxygen Species
  • Receptors, CCR7
  • interleukin-7, mouse
  • Receptor, Interferon alpha-beta
  • Streptozocin
  • Interferon-beta