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A Hypermorphic Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8 T Cells in NOD Mice.
Presa, Maximiliano Racine, Jeremy J Dwyer, Jennifer R Lamont, Deanna J Ratiu, Jeremy J Sarsani, Vishal Kumar Chen, Yi-Guang Geurts, Aron Schmitz, Ingo Stearns, Timothy
Presa, Maximiliano
Racine, Jeremy J
Dwyer, Jennifer R
Lamont, Deanna J
Ratiu, Jeremy J
Sarsani, Vishal Kumar
Chen, Yi-Guang
Geurts, Aron
Schmitz, Ingo
Stearns, Timothy
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2018-10-01
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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.
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J Immunol. 2018 Oct 1;201(7):1907-1917. doi: 10.4049/jimmunol.1800465. Epub 2018 Aug 20.
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PMC6153649
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en
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1550-6606
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Attribution-NonCommercial-ShareAlike 4.0 International