title: 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.
abstract: 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.
authors.affiliation: Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia; Food Science and Nutrition Department, National Research Center, Dokki, Cairo, Egypt.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Mahmoud
authors.affiliation: Laboratory of Immunology & Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt. Electronic address: http://www.aun.edu.eg/
authors.forename: Gamal
authors.initials: G
authors.lastname: Badr
authors.affiliation: Radiation Biology Department, National Centre for Radiation Research and Technology (NCRRT), Cairo, Egypt.
authors.forename: Badr Mohamed
authors.initials: BM
authors.lastname: Badr
authors.affiliation: Laboratory of Immunology & Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
authors.forename: Ahmad Usama
authors.initials: AU
authors.lastname: Kassem
authors.affiliation: Laboratory of Immunology & Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
authors.forename: Mahmoud Shaaban
authors.initials: MS
authors.lastname: Mohamed
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D054421:Chemokine CCL21 / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D016898:Interferon-alpha; D016899:Interferon-beta / Q000097:blood; D015851:Interleukin-7 / Q000502:physiology; D053699:Interleukin-7 Receptor alpha Subunit / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D054400:Receptors, CCR7 / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D013311:Streptozocin
chemical_list: C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; C508032:Ifnar1 protein, mouse; D016898:Interferon-alpha; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D017382:Reactive Oxygen Species; D054400:Receptors, CCR7; C576410:interleukin-7, mouse; D053633:Receptor, Interferon alpha-beta; D013311:Streptozocin; D016899:Interferon-beta
keywords: Apoptosis; CCL21, CD127, CD8+ T cell; Diabetes; Free radicals; IFN-α/β; Spleen