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

Authors

Maximiliano Presa, The Jackson LaboratoryFollow
Jeremy Racine, The Jackson LaboratoryFollow
Jennifer R Dwyer, The Jackson LaboratoryFollow
Deanna Lamont, The Jackson LaboratoryFollow
Jeremy Ratiu, The Jackson LaboratoryFollow
Vishal Kumar Sarsani, The Jackson LaboratoryFollow
Yi-Guang Chen
Aron Geurts
Ingo Schmitz
Timothy M Stearns, The Jackson LaboratoryFollow
Jennifer Allocco
Harry Chapman, The Jackson LaboratoryFollow
David V. Serreze, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

10-1-2018

JAX Source

J Immunol 2018 Oct 1; 201(7):1907-1917.

Volume

201

Issue

7

First Page

1907

Last Page

1917

ISSN

1550-6606

PMID

30127089

DOI

https://doi.org/10.4049/jimmunol.1800465

Grant

JDRF Fellowship 3PDF-2014-219-A-N & 3PDF2017-372-A-N,DRC006887, DK46266,OD020351,CA34196

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.

Recommended Citation

Presa M, Racine J, Dwyer J, Lamont D, Ratiu J, Sarsani V, Chen Y, Geurts A, Schmitz I, Stearns T, Allocco J, Chapman H, Serreze DV. A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice. J Immunol 2018 Oct 1; 201(7):1907-1917.