Faculty Collaboration Database

A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8⁺ T Cells in NOD Mice. J Immunol 2018 Oct 01;201(7):1907-1917

Date

08/22/2018

Pubmed ID

30127089

Pubmed Central ID

PMC6143397

DOI

10.4049/jimmunol.1800465

Scopus ID

2-s2.0-85053474331 (requires institutional sign-in at Scopus site)   9 Citations

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-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.

Author List

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

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Autoantigens
CD8-Positive T-Lymphocytes
Cell Differentiation
Cells, Cultured
Chromosomes, Human, Pair 7
Clonal Deletion
Diabetes Mellitus, Type 1
Disease Models, Animal
Disease Susceptibility
Humans
I-kappa B Proteins
Mice
Mice, Inbred NOD
Polymorphism, Genetic
Thymus Gland