Type 1 diabetes (T1D) is a chronic autoimmune disease that affects over 1 million people in the US. It involves the generation of T-cells that target and destroy insulin-producing cells. The thymic medullary epithelial cells (mTECs) normally train T cells to recognize the body’s own proteins. Insulin is one of several tissue-specific-antigen (TSAs) expressed by mTECs as part of this training. Its expression depends on a protein called the autoimmune regulator (Aire), which prevents autoimmunity by exposing T cells to TSAs and destroying those that react. This elimination process is called negative selection.

Aire expression in mTECs represents a critical barrier to the breakdown of T cell education in T1D. In humans and mice, Aire deficiency results in the failure of negative T cell selection and subsequent multiorgan autoimmune disease, including T1D. However, the mechanisms by which AIRE contributes to TSA expression remain incompletely characterized. Recently, a cohort of patients was identified with a particular mutation in the PHD1 domain of AIRE. My project is focused on understanding the function of PHD1 in a mouse model and how it may contribute to, or cause, the onset of T1D.

We generated a novel mouse model (called AireCY/+) with the identified mutation in the PHD1 domain. Strikingly, when compared to diabetic mice with a mutation in a different Aire domain (SAND), AireCY/+ mice had a unique pattern of affected peripheral organs, more severe neuropathy, and higher insulitis scores. Our preliminary data provide strong evidence that the PHD1 domain of Aire plays a critical role in regulating islet-specific TSAs. Therefore, we hypothesize that the PHD1 domain of Aire regulates a unique set of TSA genes which are critical for the negative selection of islet-reactive T cells.

As a postdoc fellow working with Dr. Mark Anderson at UCSF, I am focused on expanding my understanding of basic, hypothesis-driven immunology related to immune tolerance. One of my primary goals as a developing scientist is to translate knowledge from human genetics into mouse and cell models to allow dissection of T cell-mediated autoimmunity with mechanistic detail. It is my hope that this work might be harnessed for the clinical benefit of patients suffering from autoimmune diseases, such as T1D.

Click HERE to view Dr. Wang’s video.