Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid - Overexpressing NOD Mice

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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. Article Highlights:
Funding Information
  • Diabetes Research Connection (DRC 43 P21-0334 JD)
  • National Cancer Institute (P30CA034196)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK095735)

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