My research focuses on the role of a class of transcription factors called signal transducer and activator of transcription (STATs) in the differentiation and function of T helper cells. The cytokine interleukin-4 (IL-4) has long been known to be important in the development of a subset of T lymphocytes called Th2 cells and IL-4 specifically activates Stat6. We have generated Stat6-deficient mice by gene-targeting in ES cells and demonstrated that many IL-4 induced responses, including the differentiation of Th2 cells, are impaired in the absence of this STAT molecule. Similarly, the cytokine IL-12 is known to be important in the development of Th1 cells, and its effects are mediated through the Stat4 protein. We have also generated Stat4-deficient mice, and these mice have impaired IL-12 induced responses, including the differentiation of Th1 cells. Thus, despite the existence of multiple signaling pathways which are activated by cytokines such as IL-4 and IL-12, an intact STAT signaling pathway is critical for the development of Th cell subsets.

Recently, we have begun to examine how STAT proteins are regulated. Using a yeast two-hybrid screen, we have identified several proteins that appear to specifically interact with STATs. One such STAT-interacting molecule is a novel PDZ-LIM containing protein that binds to Stat4 and acts to downregulate its ability to act as a transcription factor. A second STAT-interacting molecule we have identified by yeast two-hybrid screen appears to be a protein tyrosine phosphatase. We are currently investigating the role of these molecules in STAT signaling.

Ph.D., 1988, Northwestern University