Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Immunol
2018 Oct 01;2017:1907-1917. doi: 10.4049/jimmunol.1800465.
Show Gene links
Show Anatomy links
A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice.
Presa M
,
Racine JJ
,
Dwyer JR
,
Lamont DJ
,
Ratiu JJ
,
Sarsani VK
,
Chen YG
,
Geurts A
,
Schmitz I
,
Stearns T
,
Allocco J
,
Chapman HD
,
Serreze DV
.
???displayArticle.abstract???
In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T cells recognizing pancreatic β cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-Kd and/or H2-Db class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8+ T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to 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 likely NOD-proximal chromosome 7 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 that allelic variants of Nfkbid contribute to the efficiency of intrathymic deletion of diabetogenic CD8+ T cells. However, although enhancing thymic deletion of pathogenic CD8+ T cells, ablating Nfkbid expression surprisingly accelerated T1D onset that was associated with numeric decreases in both regulatory T and B lymphocytes in NOD mice.
Aken,
The Ensembl gene annotation system.
2016, Pubmed
Aken,
The Ensembl gene annotation system.
2016,
Pubmed
Amrani,
Progression of autoimmune diabetes driven by avidity maturation of a T-cell population.
2000,
Pubmed
Annemann,
IκBNS regulates murine Th17 differentiation during gut inflammation and infection.
2015,
Pubmed
Arnold,
A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.
2012,
Pubmed
Atkinson,
Type 1 diabetes.
2014,
Pubmed
Chen,
"Agouti NOD": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells.
2005,
Pubmed
Choisy-Rossi,
Enhanced pathogenicity of diabetogenic T cells escaping a non-MHC gene-controlled near death experience.
2004,
Pubmed
Driver,
Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease.
2011,
Pubmed
Fiorini,
Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor.
2002,
Pubmed
Fosang,
Transparency Is the Key to Quality.
2015,
Pubmed
Geenen,
Thymus and type 1 diabetes: an update.
2012,
Pubmed
Ghosh,
Polygenic control of autoimmune diabetes in nonobese diabetic mice.
1993,
Pubmed
Graser,
Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions.
2000,
Pubmed
Hill,
Poly peak parser: Method and software for identification of unknown indels using sanger sequencing of polymerase chain reaction products.
2014,
Pubmed
Jeker,
Breakdown in peripheral tolerance in type 1 diabetes in mice and humans.
2012,
Pubmed
Jimi,
Differential role of the transcription factor NF-kappaB in selection and survival of CD4+ and CD8+ thymocytes.
2008,
Pubmed
Julius,
Isolation of antigen-binding cells from unprimed mice: demonstration of antibody-forming cell precursor activity and correlation between precursor and secreted antibody avidities.
1974,
Pubmed
Kishimoto,
A defect in central tolerance in NOD mice.
2001,
Pubmed
Knight,
Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity.
2013,
Pubmed
Kuwata,
IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation.
2006,
Pubmed
Lamont,
Compensatory mechanisms allow undersized anchor-deficient class I MHC ligands to mediate pathogenic autoreactive T cell responses.
2014,
Pubmed
Lieberman,
Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase.
2004,
Pubmed
McAleer,
Crosses of NOD mice with the related NON strain. A polygenic model for IDDM.
1995,
Pubmed
Miura,
The atypical IκB protein IκB(NS) is important for Toll-like receptor-induced interleukin-10 production in B cells.
2016,
Pubmed
Nejentsev,
Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.
2007,
Pubmed
Noble,
HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium.
2010,
Pubmed
Pedersen,
B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS.
2014,
Pubmed
Pedersen,
Heterozygous Mutation in IκBNS Leads to Reduced Levels of Natural IgM Antibodies and Impaired Responses to T-Independent Type 2 Antigens.
2016,
Pubmed
Pircher,
Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen.
1989,
Pubmed
Ram,
Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility.
2016,
Pubmed
Ramakrishnan,
Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice.
2016,
Pubmed
Ratiu,
Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes.
2017,
Pubmed
Schuster,
Atypical IκB proteins - nuclear modulators of NF-κB signaling.
2013,
Pubmed
Schuster,
IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor.
2012,
Pubmed
Serreze,
Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool.
2001,
Pubmed
Serreze,
Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in nonobese diabetic mice.
2008,
Pubmed
Taylor,
The design of a quantitative western blot experiment.
2014,
Pubmed
Touma,
Functional role for I kappa BNS in T cell cytokine regulation as revealed by targeted gene disruption.
2007,
Pubmed
Touma,
Impaired B cell development and function in the absence of IkappaBNS.
2011,
Pubmed
Varanasi,
Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells.
2012,
Pubmed
Verdaguer,
Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice.
1997,
Pubmed
von Boehmer,
Checkpoints in lymphocyte development and autoimmune disease.
2010,
Pubmed
Wang,
Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy.
2017,
Pubmed
