Idd5 favours robust neonatal development of highly autoreactive regulatory T cells in the NOD mouse
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PROVIDER: PRJNA1065879 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory T lymphocytes expressing the transcription factor Foxp3 (Treg) play an important role in the prevention of autoimmune diseases and other immunopathologies. Aberrations in Treg-mediated immunosuppression are therefore thought to be involved in the development of autoimmune pathologies but few have been documented. Recent reports indicated a central role for Treg developing during the neonatal period in the prevention of autoimmune pathology. We therefore investigated the development of Treg in neonatal NOD mice, an important animal model for autoimmune type 1 diabetes. Surprisingly, we found that, as compared to seven other commonly studied inbred mouse-strains, in neonatal NOD mice exceptionally large proportions of developing Treg express high levels of GITR and PD-1. The latter phenotype was previously associated with high Treg-autoreactivity in C57BL/6 mice, which we here confirm for NOD animals. Proportions of newly developing GITRhighPD-1+ Treg rapidly drop during the first week of age. A genome-wide genetic screen indicated involvement of several diabetes susceptibility loci in this trait. Analysis of a congenic mouse-strain confirmed that Idd5 contributes to the genetic control of GITRhighPD-1+ Treg-development in neonates. Our data thus demonstrate an intriguing and paradoxical correlation between an idiosyncrasy in Treg development in NOD mice and their susceptibility to type 1 diabetes.
2024-01-31 | GSE253484 | GEO
Project description:Regulatory T lymphocytes expressing the transcription factor Foxp3 (Tregs) play an important role in the prevention of autoimmune diseases and other immunopathologies. Aberrations in Treg-mediated immunosuppression are therefore thought to be involved in the development of autoimmune pathologies, but few have been documented. Recent reports indicated a central role for Tregs developing during the neonatal period in the prevention of autoimmune pathology. We therefore investigated the development of Tregs in neonatal NOD mice, an important animal model for autoimmune type 1 diabetes. Surprisingly, we found that, as compared with seven other commonly studied inbred mouse strains, in neonatal NOD mice, exceptionally large proportions of developing Tregs express high levels of GITR and PD-1. The latter phenotype was previously associated with high Treg autoreactivity in C57BL/6 mice, which we here confirm for NOD animals. The proportions of newly developing GITRhighPD-1+ Tregs rapidly drop during the first week of age. A genome-wide genetic screen indicated the involvement of several diabetes susceptibility loci in this trait. Analysis of a congenic mouse strain confirmed that Idd5 contributes to the genetic control of GITRhighPD-1+ Treg development in neonates. Our data thus demonstrate an intriguing and paradoxical correlation between an idiosyncrasy in Treg development in NOD mice and their susceptibility to type 1 diabetes.
| S-EPMC10884962 | biostudies-literature
Project description:Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell-mediated destruction of pancreatic β cells. Our previous work has shown that diabetogenic CD8 T cells in the islets of the non-obese diabetic (NOD) mouse model of T1D are phenotypically heterogenous, but CD8 T cell clonal heterogeneity in this model remains relatively unexplored. Here, we use paired single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of NOD mice. Clonal analysis of scTCR-seq data demonstrates that CD8 T cells targeting the immunodominant β cell epitope IGRP206-214 exhibit highly restricted TCR gene usage, with over 70% of IGRP206-214-reactive cells utilizing the same TCR V alpha, J alpha, and V beta genes. Despite this, we observe only 5% overlap of IGRP206-214-reactive CD8 T cell clones between two groups of 10 NOD mice, demonstrating the immense TCR heterogeneity generated by junctional diversity during V(D)J recombination. scRNA-seq identifies two new clusters of autoreactive CD8 T cells in the islets and six clusters of diabetogenic CD8 T cells in the spleen, including multiple memory-like clusters and a population of exhausted cells. Strong clonal overlap between IGRP206-214-reactive CD8 T cells in the islets and spleen suggests that these cells may exit the islets and enter the peripheral circulation. Finally, we identify correlations between TCR J beta gene usage, which is less restricted than that of other TCR genes, and CD8 T cell clonal expansion as well as effector fate. Collectively, our work demonstrates that IGRP206-214-specific CD8 T cells are phenotypically heterogeneous but clonally similar, raising the possibility of selectively targeting either conserved or divergent TCR structures of these cells for therapeutic benefit.
2022-06-02 | GSE200608 | GEO
Project description:scRNA-seq and scTCR-seq of autoreactive CD8 T cells from NOD mice
| PRJNA825521 | ENA
Project description:Total pancreatic RNA was isolated from 3 week old NOD.scid, NOD, BDC2.5/NOD and BDC2.5/NOD.scid animals by GITC method. Targets were produced using standard Affymetrix procedures from about 10ug total RNA. The data from NOD.scid, NOD, BDC2.5/NOD and BDC2.5/NOD.scid Affymetrix MGU74Av2 cel files was converted into Robust Multi Array (RMA) text file for analysis using GeneSpring 6.1 Keywords: other
2005-01-26 | GSE1623 | GEO
Project description:Transcriptional profiling of mouse bone marrow B220+CD23–CD43–IgD– autoreactive immature B cells from 3-83Igi,Rag1-/-,H-2b mice relative to non-autoreactive immature B cells from 3-83Igi,H-2d mice. Goal was to determine genes that potentially mediate negative and positive selection of immature B cells. Biological replicates: 2 autoreactive replicate against, 2 non-autoreactive replicates
2010-08-31 | E-GEOD-22802 | biostudies-arrayexpress
Project description:Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated Igµ heavy chain gene (NOD.Igµnull) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(ab’)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis.
2012-06-08 | GSE37294 | GEO
Project description:Total pancreatic RNA was isolated from 3 week old NOD.scid, NOD, BDC2.5/NOD and BDC2.5/NOD.scid animals by GITC method. Targets were produced using standard Affymetrix procedures from about 10ug total RNA. The data from NOD.scid, NOD, BDC2.5/NOD and BDC2.5/NOD.scid Affymetrix MGU74Av2 cel files was converted into Robust Multi Array (RMA) text file for analysis using GeneSpring 6.1
2007-10-12 | E-GEOD-1623 | biostudies-arrayexpress
Project description:Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated IgM-BM-5 heavy chain gene (NOD.IgM-BM-5null) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(abM-bM-^@M-^Y)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis. B cells from three independent lots of pooled spleens (n=7-8) from NOD or NR4 female mice, respectively, were purified using a magnetic-activated cell sorting (MACS) negative depletion strategy. Purified B cells from each lot were resuspended at 1x10<7> cells/ml for 2h in complete RPMI media alone or with 10M-BM-5g/ml AffiniPure goat anti-mouse IgM F(abM-bM-^@M-^Y)2 fragments. RNA was then purified from B cells and subjected to one-cycle linear amplification and biotin labeling. Two BCR-stimulated and three unstimulated NOD B cell samples plus three BCR-stimulated and three unstimulated NR4 B cell samples were hybridized to Mouse Genome 430 2.0 Arrays.
2012-06-07 | E-GEOD-37294 | biostudies-arrayexpress
Project description:Hybrid insulin peptides (HIPs) form in pancreatic beta cells through the covalent cross-linking of proinsulin peptides with various beta cell peptides, creating unique amino acid sequences not encoded in the genome. HIPs have been confidently identified in both human and mouse islets by mass spectrometry and are targeted by autoreactive T cells in type 1 diabetes (T1D) patients and disease-triggering CD4 T cells in non-obese diabetic (NOD) mice. Previous work identified cathepsin D (CatD) as an enzyme involved in HIP formation through transpeptidation reactions targeting a conserved leucine residue (L26) in the C-peptide region of proinsulin. In this study, we generated NOD mice with a leucine-to-isoleucine substitution at this position in the insulin 2 gene (NOD INS2I/I) to prevent CatD-mediated HIP formation. Mass spectrometry analysis of islet peptidomes revealed that the L26I modification effectively blocked CatD-mediated cleavage at this site and significantly reduced the levels of disease-relevant HIPs, including HIP11 and 6.9HIP. These findings were validated through T cell assays showing reduced antigenicity of islets from modified mice when exposed to HIP-reactive T cell clones. The functional consequences of reduced HIP formation were demonstrated in a year-long monitoring study, where NOD INS2I/I mice exhibited significantly delayed disease onset compared to wild-type NOD mice, with 43% versus 10% remaining disease-free after one year. In vitro experiments with human C-peptide further confirmed that the L26I substitution prevents CatD-mediated HIP formation in human samples as well. Our results establish CatD as the primary enzymatic driver of disease-relevant HIP formation and demonstrate that preventing CatD-mediated processing of proinsulin 2 C-peptide in NOD mice significantly reduces HIP formation and delays autoimmune diabetes progression, identifying a potential therapeutic target for T1D prevention.
2025-12-22 | PXD063329 | Pride