scholarly journals Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model

JCI Insight ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Brett S. Marro ◽  
Sarah Legrain ◽  
Brian C. Ware ◽  
Michael B.A. Oldstone
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Autoreactive T Cell ◽  
Diabetes Model

scholarly journals Endothelium-restricted endothelin-1 overexpression in type 1 diabetes worsens atherosclerosis and immune cell infiltration via NOX1

2020 ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Nathanne S Ferreira ◽  
Olga Berillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Aortic Arch ◽  
Vascular Complications ◽  
Cell Infiltration ◽  
Aortic Sinus ◽  
T Cell Infiltration ◽  
Perivascular Fat

Abstract Aims NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing human ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe−/−) mice enhanced high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We tested the hypothesis that ET-1 overexpression in the endothelium would worsen atherosclerosis in type 1 diabetes through a mechanism involving NOX1 but not NOX4. Methods and results Six-week-old male Apoe−/− and eET-1/Apoe−/− mice with or without Nox1 (Nox1−/y) or Nox4 knockout (Nox4−/−) were injected intraperitoneally with either vehicle or streptozotocin (55 mg/kg/day) for 5 days to induce type 1 diabetes and were studied 14 weeks later. ET-1 overexpression increased 2.5-fold and five-fold the atherosclerotic lesion area in the aortic sinus and arch of diabetic Apoe−/− mice, respectively. Deletion of Nox1 reduced aortic arch plaque size by 60%; in contrast, Nox4 knockout increased lesion size by 1.5-fold. ET-1 overexpression decreased aortic sinus and arch plaque alpha smooth muscle cell content by ∼35% and ∼50%, respectively, which was blunted by Nox1 but not Nox4 knockout. Reactive oxygen species production was increased two-fold in aortic arch perivascular fat of diabetic eET-1/Apoe−/− and eET-1/Apoe−/−/Nox4−/− mice but not eET-1/Apoe−/−/Nox1y/− mice. ET-1 overexpression enhanced monocyte/macrophage and CD3+ T-cell infiltration ∼2.7-fold in the aortic arch perivascular fat of diabetic Apoe−/− mice. Both Nox1 and Nox4 knockout blunted CD3+ T-cell infiltration whereas only Nox1 knockout prevented the monocyte/macrophage infiltration in diabetic eET-1/Apoe−/− mice. Conclusion Endothelium ET-1 overexpression enhances the progression of atherosclerosis in type 1 diabetes, perivascular oxidative stress, and inflammation through NOX1.

scholarly journals Changes in autoreactive T cell avidity during type 1 diabetes development

2009 ◽  
Vol 132 (3) ◽  
pp. 312-320 ◽  
Author(s):  
Nathan E. Standifer ◽  
Emily A. Burwell ◽  
Vivian H. Gersuk ◽  
Carla J. Greenbaum ◽  
Gerald T. Nepom
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Autoreactive T Cell ◽  
Diabetes Development

scholarly journals γ-Aminobutyric Acid Inhibits T Cell Autoimmunity and the Development of Inflammatory Responses in a Mouse Type 1 Diabetes Model

2004 ◽  
Vol 173 (8) ◽  
pp. 5298-5304 ◽  
Author(s):  
Jide Tian ◽  
Yuxin Lu ◽  
Hanwei Zhang ◽  
Cindy H. Chau ◽  
Hoa N. Dang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Inflammatory Responses ◽  
Aminobutyric Acid ◽  
Diabetes Model

scholarly journals T Cell Recognition of Autoantigens in Human Type 1 Diabetes: Clinical Perspectives

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Roberto Mallone ◽  
Vedran Brezar ◽  
Christian Boitard
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Lymphocytes ◽  
Disease Process ◽  
Immune Correlates ◽  
Autoreactive T Cell ◽  
Cell Assays ◽  
History Of ◽  
Functional Features

Type 1 diabetes (T1D) is an autoimmune disease driven by the activation of lymphocytes against pancreaticβ-cells. Amongβ-cell autoantigens, preproinsulin has been ascribed a key role in the T1D process. The successive steps that control the activation of autoreactive lymphocytes have been extensively studied in animal models of T1D, but remains ill defined in man. In man, T lymphocytes, especially CD8+T cells, are predominant within insulitis. Developing T-cell assays in diabetes autoimmunity is, thus, a major challenge. It is expected to help defining autoantigens and epitopes that drive the disease process, to pinpoint key functional features of epitope-specific T lymphocytes along the natural history of diabetes and to pave the way towards therapeutic strategies to induce immune tolerance toβ-cells. New T-cell technologies will allow defining autoreactive T-cell differentiation programs and characterizing autoimmune responses in comparison with physiologically appropriate immune responses. This may prove instrumental in the discovery of immune correlates of efficacy in clinical trials.

scholarly journals Interleukin-21 Receptor-Mediated Signals Control Autoreactive T Cell Infiltration in Pancreatic Islets

Immunity ◽  
2012 ◽  
Vol 36 (6) ◽  
pp. 1060-1072 ◽  
Author(s):  
Tom L. Van Belle ◽  
Stefan Nierkens ◽  
Ramon Arens ◽  
Matthias G. von Herrath
Keyword(s):  
T Cell ◽  
Pancreatic Islets ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Autoreactive T Cell ◽  
Interleukin 21

scholarly journals Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice

2019 ◽  
Vol 240 (3) ◽  
pp. 403-416 ◽  
Author(s):  
Yoko Yagishita ◽  
Akira Uruno ◽  
Dionysios V Chartoumpekis ◽  
Thomas W Kensler ◽  
Masayuki Yamamoto
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Critical Role ◽  
Nod Mice ◽  
Related Factor ◽  
Autoreactive T Cell ◽  
Nrf2 Activation ◽  
Ifn Γ

The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. Although activation of Nrf2 signaling is known to exert anti-inflammatory effects, the function of Nrf2 in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, which are a polygenic model of human type 1 diabetes, to generate a genetic model for assessment of the contribution of Nrf2 activation to prevention and/or treatment of type 1 diabetes. Because Keap1 (Kelch-like ECH-associated protein 1) negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout Keap1 alleles, which enhanced Nrf2 signaling to moderate or excess levels, respectively. Nrf2 activation in the NOD::Keap1 FA/– mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion and prevented the development of diabetes mellitus. Notably, Nrf2 activation decreased both the plasma interferon-γ (IFN-γ) levels and the IFN-γ-positive cell numbers in the pancreatic islets. The amelioration of diabetes was also observed in the NOD mice with two hypomorphic Keap1 alleles (Keap1FA/FA) by intermediate activation of Nrf2. Both NOD::Keap1FA/– and NOD::Keap1FA/FA mice had a decreased incidence of diabetes mellitus, demonstrating that activation of Nrf2 signaling prevented the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for the prevention and treatment of type 1 diabetes.

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