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

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

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Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope

Journal of Experimental Medicine ◽

10.1084/jem.20110574 ◽

2011 ◽

Vol 208 (7) ◽

pp. 1501-1510 ◽

Cited By ~ 93

Author(s):

Carolin Daniel ◽

Benno Weigmann ◽

Roderick Bronson ◽

Harald von Boehmer

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Nod Mice ◽

Nonobese Diabetic ◽

Cell Clones ◽

Autoimmune Attack ◽

Agonistic Activity ◽

Novel Strategy

Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.

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Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice

BMC Microbiology ◽

10.1186/s12866-021-02406-9 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Eric Marietta ◽

Irina Horwath ◽

Stephanie Meyer ◽

Shahryar Khaleghi-Rostamkolaei ◽

Eric Norman ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Nod Mice ◽

Histopathological Analysis ◽

Microbial Composition ◽

Time Points ◽

Pancreatic Lymph Nodes

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5–8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. Results Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. Conclusions These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

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Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells

The FASEB Journal ◽

10.1096/fj.201900146r ◽

2019 ◽

Vol 33 (7) ◽

pp. 8241-8248 ◽

Cited By ~ 6

Author(s):

Zhixia Li ◽

Xiajie Shi ◽

Junbin Liu ◽

Feng Shao ◽

Gan Huang ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice

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Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

Infection and Immunity ◽

10.1128/iai.01170-08 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5347-5358 ◽

Cited By ~ 87

Author(s):

Qian Liu ◽

Krishnan Sundar ◽

Pankaj K. Mishra ◽

Gity Mousavi ◽

Zhugong Liu ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Helminth Infection ◽

Inflammatory Responses ◽

Nod Mice ◽

Interleukin 4 ◽

Heligmosomoides Polygyrus ◽

Nonobese Diabetic

ABSTRACT Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4+ CD25+ FoxP3+ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4+ CD25+ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25- and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

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

10.1101/258525 ◽

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

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