Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid- Overexpressing NOD Mice.
Document Type
Article
Publication Date
5-1-2026
Original Citation
Dwyer J,
Racine J,
Chapman H,
Bell A,
Quinlan A,
Stafford G,
Serreze DV.
Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid- Overexpressing NOD Mice. Diabetes. 2026;75(5):816–24.
Keywords
JMG, SS1, Animals, Diabetes Mellitus, Type 1, Mice, Inbred NOD, Mice, T-Lymphocytes, Regulatory, Mice, Transgenic, Dendritic Cells, Female, CD8-Positive T-Lymphocytes, B-Lymphocytes, Islets of Langerhans
JAX Source
Diabetes. 2026;75(5):816–24.
ISSN
1939-327X
PMID
41860446
DOI
https://doi.org/10.2337/db25-0956
Grant
National Institutes of Health grant DK095735 to D.V.S.
Abstract
We previously reported that transgenic overexpression of Nfkbid in NOD mice led to robust type 1 diabetes protection associated with enhanced negative selection of autoreactive T cells and expansion of regulatory T cells (Tregs) with increased suppressive capacity. The goal of this study was to further identify cellular and molecular mechanisms underlying strong protection from type 1 diabetes imbued by overexpressing Nfkbid. Transcript analysis of Tregs from Nfkbid-overexpressing NOD mice show enrichment of cellular replication pathways. Effector T cells from Nfkbid-overexpressing NOD mice have increased indicators of activation-induced exhaustion in pancreatic lymph nodes and islets. This trait is intrinsic to Nfkbid-overexpressing T cells, as ex vivo anti-CD3 stimulation of splenic-derived T cells can reproduce this phenotype. Anti-PD-1 administration breaks the diabetes protective effect. Furthermore, we found that Nfkbid-overexpressing dendritic cells, but not B cells, have an enhanced capacity to stimulate proliferation of diabetogenic AI4 CD8+ T cells (with wild-type levels of Nfkbid). Conversely, B cells, but not dendritic cells, drive enhanced de novo conversion of regulatory T cells from effector T cells. Together, this study documents additional mechanisms that likely synergize to contribute to the diabetes-protective effects of Nfkbid overexpression. Understanding the mechanisms underlying protection from Nfkbid overexpression may lead to novel therapeutic avenues.