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Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid Overexpressing NOD mice

ABSTRACT: Transgenic overexpression of Nfkbid in NOD mice causes robust type 1 diabetes protection associated with expansion of Tregs with increased suppressive capacity. Complementarily, Nfkbid ablation leads to decreased Treg numbers, decreased suppressive capacity and accelerated diabetes.The goal of this experiment was to further identify molecular mechanisms underlying strong protection and susceptibility from type 1 diabetes imbued by modifying Nfkbid expression. mRNA sequencing analysis of Tregs from NOD mice with absent or overexpressed Nfkbid was performed. Differential gene expression was calculated and Ingenuity Pathway analyses showed enrichment of cellular replication pathways. Understanding the mechanisms underlying protection from Nfkbid overexpression may lead to novel therapeutic avenues.

ORGANISM(S): Mus musculus

PROVIDER: GSE315028 | GEO | 2026/05/01

REPOSITORIES: GEO

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Nfkbid represents an Idd7 locus gene contributing to impaired thymic deletion of CD8 T-cells in NOD mice

Project description:In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic ß-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8 T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant as a strong candidate for an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T-cells. These results indicated allelic variants of Nfkbid represent an Idd7 gene contributing to the efficiency of intrathymic deletion of diabetogenic CD8+ T-cells. However, while enhancing thymic deletion of pathogenic CD8+ T-cells, ablation of Nfkbid expression surprisingly accelerated T1D onset in NOD mice likely by numerically decreasing regulatory T- and B-lymphocytes (Tregs/Bregs), thereby reducing their peripheral immunosuppressive effects. We used microarray analysis to identify differentialy expressed genes in thymus under conditions of induced thymic negative selection. We compare two mice strains, NOD-LCMV vs NOD.Ln82-LCMV (a congenic stock for a C57BL/6 derived segment delimited by markers D7Mit117–D7Mit247).

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Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid Overexpressing NOD mice

Project description:Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid Overexpressing NOD mice

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Nfkbid-overexpression and -ablation enhances thymic deletion of autoreactive AI4 CD8 T-cells

Project description:Purpose: Analyze genes involved in the negative selection of CD4CD8 double positive thymocytes from NOD-AI4 control mice, NOD-AI4-Nfkbid-/- (KO) and NOD-AI4-60A undergoing negative selection. Methods: RNA-Seq based gene expression analyses were used to identify differentially expressed genes in CD4CD8 double positive thymocytes from NOD-AI4 (control), NOD-AI4-Nfkbid-/- (KO) and NOD-AI4-60A undergoing negative selection.

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