Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

Gagnerault, Marie‐Claude; Luan, Jian Jian; Lotton, Chantal; Lepault, Françoise

doi:10.1084/jem.20011353

Cited by 274 publications

(266 citation statements)

References 29 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…Intra-islet dendritic cells must encounter very large quantities of insulin, both secreted and contained in granules of beta cells, such that the number of processed and presented peptides is of a sufficient threshold to activate insulin reactive T cells. This idea is supported by evidence that early diabetogenic T cell priming occurs in the draining peri-pancreatic lymph node, where naïve T cells encounter APCs charged with abundant betacell antigens [42,43]. A second component that most likely plays a role in resolving the apparent paradox between the failure of negative selection and peripheral activation is that of costimulation.…”

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thmentioning

confidence: 95%

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

View full text Add to dashboard Cite

One seminal aspect in autoimmune diabetes is antigen presentation of beta cell antigens by the diabetes-propensity class II histocompatibility molecules. The binding properties of I-A g7 molecules are reviewed here and an emphasis is placed on their selection of peptides with a highly specific sequence motif, in which one or more acidic amino acids are found at the carboxy end interacting at the P9 anchoring site of I-A g7 . The reasons for the central role of I-A g7 in the autoimmune response are analyzed. The insulin B chain segment 9-23 is a hot spot for T cell selection and a striking example of a weak MHC binding peptide that triggers autoreactivity.

show abstract

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thmentioning

confidence: 95%

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

View full text Add to dashboard Cite

show abstract

“…The primary activation of diabetogenic CTLs occurs within the pancreatic and gut-associated lymph nodes (LNs) [16,17]. Lymphocytes within the pancreatic LNs thus communicate with the intestinal immune system, and the gut and its luminal contents may contribute to the initiation of type 1 diabetes [18].…”

Section: Introductionmentioning

confidence: 99%

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes. Methods Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [ΔespF]) of causing intestinal epithelial barrier disruption. Results Here we demonstrate that prediabetic (12-weekold) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting ΔespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8 + T cells, compared with uninfected NOD mice. Conclusions/interpretation This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8 + T cells and modulates insulitis.

show abstract

“…The PPLNs are the site for initial priming and expansion of diabetogenic T cells (23)(24)(25). Pools of natural peptides, each containing 4 -9 different peptides, were used to stimulate PPLN cells in the presence of NOD splenic APCs and IL-2.…”

Section: Searching For T Cells To the Selected Peptidesmentioning

confidence: 99%

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri¹,

Walters

Rohrs

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

The diversity of Ags targeted by T cells in autoimmune diabetes is unknown. In this study, we identify and characterize a limited number of naturally processed peptides from pancreatic islet β-cells selected by diabetogenic I-Ag7 molecules of NOD mice. We used insulinomas transfected with the CIITA transactivator, which resulted in their expression of class II histocompatibility molecules and activation of diabetogenic CD4 T cells. Peptides bound to I-Ag7 were isolated and examined by mass spectrometry: some peptides derived from proteins present in secretory granules of endocrine cells, and a number were shared with cells of neuronal lineage. All proteins to which peptides were identified were expressed in β cells from normal islets. Peptides bound to I-Ag7 molecules contained the favorable binding motif characterized by acidic amino acids at the P9 position. The draining pancreatic lymph nodes of prediabetic NOD mice contained CD4 T cells that recognized three different natural peptides. Furthermore, four different peptides elicited CD4 T cells, substantiating the presence of such self-reactive T cells. The overall strategy of identifying natural peptides from islet β-cells opens up new avenues to evaluate the repertoire of self-reactive T cells and its role in onset of diabetes.

show abstract

Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

Cited by 274 publications

References 29 publications

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Contact Info

Product

Resources

About