Description of Research Expertise

Research Interests: T cell signal transduction and the regulation of T cell differentiation

T cells integrate multiple signals from their environment, and the culmination of these signals direct how CD4 and CD8 T cells differentiate. My lab uses a variety of in vivo model systems to understand how distinct pathways and proteins regulate T cell fates. 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 investigating the underlying mechanisms by which TET2 and other DNA methylation modifying enzymes regulate T cell differentiation.

• When T cells are continually exposed antigen, as in the setting of chronic viral infection or cancer, they can become “exhausted.” Exhausted T cells (Tex) are characterized by high expression of inhibitory receptors and loss of robust effector function. How T cell signaling pathways regulate the differentiation of Tex cells during chronic antigen exposure is not fully known. To bridge this gap in knowledge, we are exploring the role of signaling proteins, including NFkB family members, in the establishment and persistence of CD8 T cell exhaustion. In collaboration with Dr. Warren Pear’s lab, we have identified the pseudokinase, Trib1, as a negative regulator of T cell activation and have defined a role for this scaffolding protein in regulating Tex cell differentiation. Future work aims to define the molecular mechanism underlying these findings as well as further defining how Trib1 regulates T cell differentiation in other settings.

• Exposure to chronic antigen stimulation also impacts CD4 T cell differentiation and function. Using similar approaches previously used to defining CD8 T cell exhaustion, we are currently investigating the molecular mechanisms that contribute to CD4 T cell exhaustion.