Natural Protection From Type 1 Diabetes in Non Obese Diabetic (Nod) Mice is Characterized by a Unique Pancreatic Islet Phenotype

10.2337/figshare.13643393 ◽

2021 ◽

Author(s):

Joanne Boldison ◽

Terri C. Thayer ◽

Joanne Davies ◽

F. Susan Wong

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Pancreatic Islets ◽

Pancreatic Islet ◽

Nod Mice ◽

Significant Shift ◽

Immune Infiltrate ◽

Cell Compartments ◽

Natural Protection

The non-obese diabetic (NOD) mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally-protected from developing diabetes, and currently studies characterising this cohort are very limited. Here, using both immunofluorescence and multi-parameter flow cytometry we focus on the pancreatic islet morphology and immune infiltrate observed in naturally-protected NOD mice. We show that naturally-protected NOD mice are characterised by an increased frequency of insulin-containing, smaller sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed towards a regulatory phenotype in both T and B-cell compartments. Pancreatic islets have an increased frequency of IL-10 producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift towards reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally-protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.

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Natural Protection From Type 1 Diabetes in Non Obese Diabetic (Nod) Mice is Characterised by a Unique Pancreatic Islet Phenotype

Diabetes ◽

10.2337/db20-0945 ◽

2021 ◽

pp. db200945

Author(s):

Joanne Boldison ◽

Terri C. Thayer ◽

Joanne Davies ◽

F. Susan Wong

Keyword(s):

Type 1 Diabetes ◽

Pancreatic Islet ◽

Nod Mice ◽

Natural Protection

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Faculty Opinions recommendation of Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1122821.580959 ◽

2008 ◽

Author(s):

Jin-Xiong She

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice

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Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset

Science Immunology ◽

10.1126/sciimmunol.aaw6329 ◽

2019 ◽

Vol 4 (38) ◽

pp. eaaw6329 ◽

Cited By ~ 9

Author(s):

Louis Gioia ◽

Marie Holt ◽

Anne Costanzo ◽

Siddhartha Sharma ◽

Brian Abe ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Disease Onset ◽

Insulin Response ◽

Nod Mice ◽

Class Ii ◽

Single Amino Acid ◽

Specific Gene ◽

Single Amino Acid Change

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.

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Therapy of type 1 diabetes with CD4+CD25highCD127-regulatory T cells prolongs survival of pancreatic islets — Results of one year follow-up

Clinical Immunology ◽

10.1016/j.clim.2014.03.016 ◽

2014 ◽

Vol 153 (1) ◽

pp. 23-30 ◽

Cited By ~ 179

Author(s):

Natalia Marek-Trzonkowska ◽

Małgorzata Myśliwiec ◽

Anita Dobyszuk ◽

Marcelina Grabowska ◽

Ilona Derkowska ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Pancreatic Islets ◽

One Year

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Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

10.1101/2020.02.06.937839 ◽

2020 ◽

Author(s):

Heejoo Kim ◽

Jelena Perovanovic ◽

Arvind Shakya ◽

Zuolian Shen ◽

Cody N. German ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Target Genes ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Cell Receptor ◽

Glucose Levels ◽

Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

10.2337/figshare.12245363.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

10.2337/figshare.12245363 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

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CD70 Inversely Regulates Regulatory T Cells and Invariant NKT Cells and Modulates Type 1 Diabetes in NOD Mice

The Journal of Immunology ◽

10.4049/jimmunol.2000148 ◽

2020 ◽

Vol 205 (7) ◽

pp. 1763-1777

Author(s):

Cheng Ye ◽

Benjamin E. Low ◽

Michael V. Wiles ◽

Todd M. Brusko ◽

David V. Serreze ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice ◽

Nkt Cells ◽

Invariant Nkt Cells

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Faculty Opinions recommendation of IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5308957.5255055 ◽

2010 ◽

Author(s):

Paul Gleeson

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice ◽

Local Effect

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