| First Author | Presa M | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 7 | Pages | 1907-1917 |
| PubMed ID | 30127089 | Mgi Jnum | J:265223 |
| Mgi Id | MGI:6199239 | Doi | 10.4049/jimmunol.1800465 |
| Citation | Presa M, et al. (2018) A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8(+) T Cells in NOD Mice. J Immunol 201(7):1907-1917 |
| abstractText | In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8(+) T cells recognizing pancreatic beta cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-K(d) and/or H2-D(b) 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. |
