89-OR: Type 1 Interferons Inhibition of Interleukin-10 Signaling in T Cells in Type 1 Diabetes Development

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 89-OR
Author(s):  
MARCOS IGLESIAS LOZANO ◽  
MARIA CHICCO ◽  
DARREL A. BIBICHEFF ◽  
GERALD BRANDACHER ◽  
GIORGIO RAIMONDI
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Interleukin 10 ◽  
Diabetes Development ◽  
Type 1 Interferons

scholarly journals Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

2018 ◽  
Author(s):  
Marcos Iglesias ◽  
Anirudh Arun ◽  
Maria Chicco ◽  
Brandon Lam ◽  
Conover Talbot ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Nod Mice ◽  
Interleukin 10 ◽  
Type I Interferons ◽  
Type I ◽  
Diabetes Development

AbstractDestruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in NOD mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.AbbreviationsALNaxillary lymph nodesIL-10interleukin-10MFImean fluorescence intensityMLNmesentheric lymph nodesNODnonobese diabetic micePLNpancreatic lymph nodesTI-IFNtype-1 InterferonsTmemmemory T cellsTregregulatory T cells

scholarly journals Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice

2019 ◽  
Vol 9 ◽  
Author(s):  
Ivan Koprivica ◽  
Milica Vujičić ◽  
Dragica Gajić ◽  
Tamara Saksida ◽  
Ivana Stojanović
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Ethyl Pyruvate ◽  
Diabetes Development

scholarly journals Peptidylarginine deiminase inhibition prevents diabetes development in NOD mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Fernanda M. C. Sodré ◽  
Samal Bissenova ◽  
Ylke Bruggeman ◽  
Ronak Tilvawala ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Effector Memory ◽  
Cell Reactivity ◽  
Diabetes Development ◽  
T Cell Reactivity

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4<sup>+</sup> T cells and a modest reduction in the frequency of IFNγ-producing CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

scholarly journals The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

2020 ◽  
Vol 6 (42) ◽  
pp. eabc5586 ◽  
Author(s):  
Christine Bender ◽  
Teresa Rodriguez-Calvo ◽  
Natalie Amirian ◽  
Ken T. Coppieters ◽  
Matthias G. von Herrath
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cd8 T Cells ◽  
Human Pancreas ◽  
Healthy Individuals ◽  
High Frequencies ◽  
Histocompatibility Complex ◽  
Diabetes Development ◽  
Specific Trigger

Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8+ T cells from healthy individuals. We quantified PPI-specific CD8+ T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8+ T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8+ T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system.

scholarly journals Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development

2007 ◽  
Vol 37 (8) ◽  
pp. 2234-2241 ◽  
Author(s):  
Megan S. Ford ◽  
Wenhao Chen ◽  
Sophie Wong ◽  
Carmen Li ◽  
Ramesh Vanama ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Double Negative ◽  
Diabetes Development ◽  
Double Negative T Cells

scholarly journals Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

2017 ◽  
Vol 9 (402) ◽  
pp. eaaf7779 ◽  
Author(s):  
Mohammad Alhadj Ali ◽  
Yuk-Fun Liu ◽  
Sefina Arif ◽  
Danijela Tatovic ◽  
Hina Shariff ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Immune Modulation ◽  
Cell Function ◽  
Human Leukocyte ◽  
Foxp3 Expression ◽  
Interleukin 10 ◽  
Β Cell ◽  
C Peptide

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

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