Description of Research Expertise

Research Interests:
T cell signal transduction and its regulation of thymocyte development and T cell differentiation

T cells integrate multiple signals from their environment. The culmination of these signals direct the fate of developing thymocytes, dictating the outcome of thymocyte selection and T-regulatory (Treg) cell development. Mature peripheral T cells also integrate multiple signaling pathways during encounter with pathogens and are directed to differentiate into one of several T cell effector subsets.

We are interested in understanding how specific pathways direct these differentiation steps in thymocytes and peripheral T cells. Currently we are focusing on signaling pathways and epigenetic modifiers that have recently been implicated in T cell lymphomagenesis with an aim towards understanding how these pathways and enzymes direct both normal and malignant T cell biology. Some active areas of investigation include the following:

• T cell activation leads to transient changes in the activation states of many proteins and enzymes, but it also results in heritable changes at the epigenetic level. DNA methylation is a common epigenetic modification that is regulated via both active and passive mechanisms. TET2 is a methylcytosine dioxgenase involved in the active demethylation of DNA and is frequently mutated in a specific class of T cell lymphomas. Our lab has shown that TET2 regulates the development of memory CD8+ T cells as well as CD4+ T cell differentiation. We are currently identifying the targets of TET2 to understand the mechanism by which it regulates T cell differentiation. We are also interested in CXXC5, a negative regulator of TET2, to determine its TET2 –dependent and –independent functions in T cell activation and differentiation.

• The GTPase RhoA is important for thymocyte development and is activated downstream of the T cell receptor and integrins. RhoA regulates actin reorganization and has been implicated in T cell metabolism. Recently, RhoA mutations have been identified in T cell lymphomas, often co-occurring with TET2 loss-of-function mutations. Using both in vitro and in vivo models of regulated RhoA expression, we are investigating the mechanism of RhoA function in healthy and diseased states.