Project Description

We know that multiple cell types contribute to the onset of Type 1 Diabetes (T1D), which strikes when the body’s immune system attacks insulin-producing beta cells in the pancreas. We also know that one category of T-cells (known as CD8+ T-cells) seems to be particularly lethal. Understanding what gives rise to this class of autoreactive T-cells is an important research question for our lab.

Studies in mice have revealed that variants of MHC/HLA genes also play a role in the development of T1D. Interestingly, these variants are also found in healthy mice and humans. However, when these mutant genes are combined with other genetic factors associated with T1D vulnerability, the result is an increase in the destructive CD8+ T-Cells.

We have also learned through genetic mapping in mice that differential expression of a gene called Nfkbid affects levels of CD8+ T-cells during T-cell development and impact the activity of regulatory T-cells (known as Tregs), a class of cells with the capacity to suppress autoreactive T-cells.

Using CRISPR gene-editing technology, we eliminated expression of Nfkbid in mice. This experiment resulted in a dramatic acceleration of T1D progression and a massive reduction in Tregs – the immune cells that seem to be a bulwark against harmful T-cells. Conversely, elevating expression of Nfkbid led to complete T1D resistance. The findings suggest that removing CD8+ T-cells and increasing Tregs confers T1D protection, however the biological mechanisms underlying those outcomes remain unknown.

DRC funding will enhance the understanding of how Nfkbid expression levels affect both the removal of autoreactive CD8+ T-cells and Treg numbers and function and will help us better understand the molecular networks potentially dysregulated in human T1D.

Click HERE to watch Dr. Dwyer’s video.