Our Goals
Project 1: Function and regulation of Treg cells
Treg cells, a CD4 T cell subset that specifically expresses a transcription factor Foxp3, are critical to suppress immune responses to maintain self-tolerance. I became interested in studying the function of regulatory T cells when I was a postdoc at Yale University. I developed genetic modified mice to trace Treg cells (PNAS, 2005) and revealed a novel mechanism through which their function is controlled (Nature, 2007). After establishing my own research group here at UNC, I continued investigating how Treg cell function is controlled. We found that a transcription factor GATA-3 is highly expressed in Treg cells and controls Treg cell function and immune homeostasis. Mechanistically, GATA-3 controls the expression of Foxp3 (Journal of Immunology, 2010; Immunity, 2011). We revealed how Treg function is controlled during immunological aging (Journal of Clinical Investigation, 2020) and molecular mechanisms underlying Treg cell function (2021, Nature). We are investigating how Treg cell function is controlled during immunity, autoimmunity and cancer.
Treg cells suppress immune responses
The overarching goal of our research is to uncover critical mechanisms underlying T cell function in immune homeostasis, immunological aging, immunity, and immune diseases including autoimmunity and cancer. We seeks novel and improved ways to treat diseases by targeting T cells.
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Publication List:
Project 2: TGF-beta signaling controlled T cell function
Initially identified as a tumor promoting factor, transforming growth factor beta (TGF-beta) is essential for immune suppression. As important as TGF-beta in T cells, how the signaling downstream of TGF-beta receptor controls T cell function remains. Our laboratory has generated mouse models where various components of TGF-beta signaling pathways are abrogated in T cells. As a postdoc, I found that the ‘non-canonical’ TGF-beta signaling pathway is critical for T cell function (Nature Immunology 2006). My research group at UNC-CH found that the ‘canonical’ TGF-beta signal pathway was indeed important to control T cell function but in a different way from ‘non-canonical’ TGF-beta signaling pathway (PNAS, 2012). In addition, we found that interfering with ‘canonical’ and ‘non-canonical’ TGF-beta signaling pathways using genetic or pharmacological approaches was beneficial to treat inflammatory diseases, (Cellular and Molecular Immunology, 2011, Journal of Immunology, 2012, Frontiers in Immunology, 2019). Our laboratory revealed an unexpected TGF-beta-independent role for Smad4 in controlling T cell function (Immunity, 2015). While TGF-beta signaling is central to control Th17 cell differentiation, the mechanisms is unclear, we discovered that TGF-beta superfamily and SKI/Smad4 complex is critical to inhibit Th17 cell differentiation (Nature, 2017; Molecular Immunology 2019; Frontiers Immunology, 2021; Immunity, 2021). These findings collectively suggest that TGF-beta signaling controls T cell function through mechanisms much more complex and intricate than we thought. Much remains to be revealed as how TGF-beta superfamily signaling controls T cell function during diseases such as cancer and autoimmunity.
Diverse function of TGF-beta in immunity
Project 3: Molecular network underlying of T cell differentiation and function
Under steady state, most mature T cells remain in quiescence with little growth (biomass increase due to elevated metabolism and biosynthesis) or proliferation. For T cells to mount effective response after antigenic stimulation, they must exit quiescence, entry cell cycle, proliferate rapidly, and differentiate into cells with specialized function. This well-orchestrated process is imperative for normal immune function. I have long been interested in addressing how these processes are controlled. As a PhD student, by developing a new transgenic mouse model (PNAS, 2000), I have revealed how the TCR signaling pathway and cell cycle regulators crosstalk to control T cell proliferation and survival (Immunity, 2003). We uncovered an unexpected function of Smad4 in promoting T cell growth and proliferation and T cell mediated immune response (Immunity, 2015). Using quantitative proteomics, we found that GATA3 is critical for T cell proliferation in response to viral infection (Nature Immunology, 2013) and RASA3 directs Th17 cell differentiation (Immunity, 2018). We found that HIV protein r binding protein (VprBP, also known as DCAF1) is essential for activation induced T cell growth, cell cycle entry and proliferation (Nature Communications, 2016) and controls Treg cell senescence during immunological aging (JCI, 2020). Using the comprehensive experimental systems established in our laboratory, we are making progress in identifying critical factors and molecular mechanisms controlling T cell function.
Central roles for T cells in health and diseases
Molecular control of Th cell differentiation
