Document Type
Article
Publication Date
11-1-2025
Original Citation
Racine J,
Dwyer J,
Chapman H,
Bell A,
Robledo RF,
Serreze DV.
Direct-in-NOD genetic ablation of Bcl3 leads to complete type 1 diabetes protection. J Immunol. 2025;214(11):2847–60.
Keywords
JMG, SS1, Animals, Mice, Diabetes Mellitus, Type 1, B-Cell Lymphoma 3 Protein, Mice, Knockout, Mice, Inbred NOD, Mice, Inbred C57BL, T-Lymphocytes, Regulatory, B-Lymphocytes, Spleen, Lymph Nodes
JAX Source
J Immunol. 2025;214(11):2847–60.
ISSN
1550-6606
PMID
40796308
DOI
https://doi.org/10.1093/jimmun/vkaf189
Grant
J.R.D. was supported by Diabetes Research Connection grant DRC 43 P21-0334 JD. D.V.S. was supported by National Institutes of Health grant R01 DK095735. Technical support on this application was supported by National Cancer Institute award P30 CA034196 to The Jackson Laboratory.
Abstract
It was previously reported that genetic ablation of the NF-κB atypical inhibitor Bcl3 through congenic introduction of a 129P2-embryo derived knockout allele (Bcl3tm1Ver) accelerated autoimmune diabetes in the NOD mouse model. Conversely, we found that direct CRISPR-mediated ablation of this gene in the NOD/ShiLtDvs substrain completely inhibited diabetes development. Our CRISPR approach excised exons 3-7 within the NOD Bcl3 gene. These new NOD-Bcl3-/- mice had very low levels of insulitis, indicating protective mechanisms elicited early in the disease process. Dissimilar to reports of Bcl3 ablation in nonautoimmune C57BL/6-background mice, we found that splenic and lymph node B cells were not reduced. However, splenic T2 and MZ cells were increased with a disruption of B-cell follicle formation. Diabetes protection was associated with elevated splenic and lymph node regulatory T cells, and increases in CD4 effector and CD8 central memory T cells in pancreatic lymph nodes. Diabetes protection was overridden by anti-PD-1 administration. Previous studies suggested that Bcl3 may influence diabetes development downstream of Nfkbid, another atypical NF-κB inhibitor. Indeed, co-introduction of this Bcl3 knockout allele also completely blocked diabetes in NOD-Nfkbid-/- mice normally characterized by accelerated disease. Collectively these findings support the possibility that prior findings may have been driven by congenic introduction of linked modifier genes from non-NOD background strains and initiate a critical reevaluation of the role of Bcl3 in type 1 diabetes pathogenesis.
Creative Commons License
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