Our research goal is to elucidate the cellular and molecular mechanisms regulating the immune response in health and disease including infectious diseases, autoimmune diseases and cancer. Currently, we are particularly interested in understanding the dynamic role of one subpopulation of T cells, namely CD4+CD25+FOXP3+ regulatory T cells (FOXP3+Tregs), in major human infectious diseases.
The level and activity of the forkhead family transcription factor FOXP3 determine the immune function of FOXP3+Tregs. At the beginning of infectious processes, FOXP3+Tregs may regulate effector immune cell responses and lead to failure to control infection. FOXP3+Tregs may also help to limit collateral tissue damage when the antiviral immune responses are too vigorous. Understanding the regulation of FOXP3 and the dynamic ensemble of FOXP3 with enzymatic cofactors in Tregs will provide therapeutic applications for major human viral infectious diseases including HIV, hepatitis B and C viruses.
Based on previous findings (Reviewed in Immunol Rev 212:99-113; Curr Opin Immunol 19(5):589-95; Cell Cycle 15;6(12):1432-6; and Immunology 123(1):17-9), we hypothesize that in both FOXP3+Tregs and FOXP3+ epithelial cells, 1) FOXP3 is highly regulated in a spatial and temporal manner in response to physiological signals during viral infection; 2) the function of FOXP3 is dependent on its posttranslational modification status; 3) the function of FOXP3 is also dependent on its dynamic ensemble with other binding partners, including several key transcription factors and enzymatic co-repressors and/or co-activators.
In order to test the hypothesis and elucidate the function of FOXP3+Tregs in infectious diseases, we will combine molecular, biochemical, structural, cellular and mouse genetic tools to work on the following projects:
- To identify the binding partners, upstream regulators and downstream effectors of FOXP3 and analyze their function in modulating Treg activity in infectious diseases;
- To study signal-dependent spatial and temporal regulation of FOXP3 level, activity and ensemble during infectious processes;
- To examine activity-dependent post-translational modifications of FOXP3 and the functional consequences in response to various viral infection.