Autoimmune rheumatic diseases, which constitute a broad range of chronic illnesses, cause significant morbidity and mortality in the US and worldwide. T cell antigen receptor (TCR) recognition and signaling have long be recognized to play a critical role in the pathogenesis of autoimmune diseases. However, how altered TCR signaling strength affects immune tolerance and promotes autoimmunity remains incompletely understood. The major goal of Dr. Shen’s laboratory is to understand how abnormal TCR signaling resulting from mutations from human patients with immune dysregulated disorders may alter T cell antigen sensitivity and impair immune tolerance. Studying human monogenic diseases with known genetic defects and autoimmune phenotypes provides us with a unique opportunity for advancing our knowledge of disease pathogenesis of more common polygenic autoimmune diseases. These studies may also have implications in preventing cancer immunotherapy related adverse events and identification of new therapeutic targets for autoimmune diseases.