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J Immunol. 2018 Oct 1;201(7):1907-1917. doi: 10.4049/jimmunol.1800465. Epub 2018 Aug 20.

A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice.

Author information

1
The Jackson Laboratory, Bar Harbor, ME 04609.
2
Medical College of Wisconsin, Milwaukee, WI 53226.
3
Systems-Oriented Immunology and Inflammation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and.
4
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
5
The Jackson Laboratory, Bar Harbor, ME 04609; dave.serreze@jax.org.

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.

PMID:
30127089
PMCID:
PMC6143397
[Available on 2019-10-01]
DOI:
10.4049/jimmunol.1800465

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