T cells are key to the ability of the immune system to control infection, cancer and prevention of autoimmunity. However, in chronic disease, such as chronic Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) infection, hepatocellular carcinoma (HCC), or inflammatory bowel disease (IBD), T cell functionality is altered and inefficient in preventing pathology.

We are interested in how the T cell response is regulated during chronic disease and how immunotherapeutic interventions can augment function.

A major focus in the lab is centered on understanding exhausted T cells (TEX), which constitute a T cell lineage distinct from functional memory and effector cells that is characterized by co-expression of immunoregulatory molecules, an altered transcriptional and epigenetic landscape and reduced effector and memory functionality. We have recently demonstrated that bioenergetic regulation through immune checkpoints (e.g., PD-1) is an important driver of exhaustion. Further, we have demonstrated heterogeneity and disease associations of different varieties of exhausted T cells in humans that are impacted by therapy.

Our translational research is currently focused on chronic HBV and HCV infection and HCC. We interrogate TEX prior to and during antiviral or checkpoint therapies (e.g., anti-PD-1, anti-CTLA-4) using both targeted and systems immunology approaches. We further aim to dissect the impact of metabolic regulation through integration of signaling via immunoregulatory receptors and environmental factors on T cell exhaustion. Understanding the regulation of exhausted T cells has major implications for immunotherapeutic approaches in infection, cancer and autoimmunity.