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dc.contributor.authorPresa, Maximiliano
dc.contributor.authorRacine, Jeremy J
dc.contributor.authorDwyer, Jennifer R
dc.contributor.authorLamont, Deanna J
dc.contributor.authorRatiu, Jeremy J
dc.contributor.authorSarsani, Vishal Kumar
dc.contributor.authorChen, Yi-Guang
dc.contributor.authorGeurts, Aron
dc.contributor.authorSchmitz, Ingo
dc.contributor.authorStearns, Timothy
dc.contributor.authorAllocco, Jennifer
dc.contributor.authorChapman, Harold D
dc.contributor.authorSerreze, David V
dc.identifier.citationJ Immunol. 2018 Oct 1;201(7):1907-1917. doi: 10.4049/jimmunol.1800465. Epub 2018 Aug 20.en_US
dc.description.abstractIn 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.en_US
dc.publisherAmerican Association of Immunologistsen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.titleA Hypermorphic Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8 T Cells in NOD Mice.en_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalJournal of Immunologyen_US
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)

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