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.
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