Migration of normal and transformed lymphocytes
How are the chemotactic gradients that guide immune cells established? How does T cell residence time in tissues affect the immune response?
Much of our focus has been on how gradients of the signaling lipid sphingosine 1-phosphate (S1P) are established. S1P’s most fundamental role in the immune system is to guide cells out of tissues into circulation. In most cases, the concentration of S1P is higher in blood and lymph than in tissues, and leukocytes follow these S1P gradients out of tissues into blood and lymph vessels. We have developed novel tools to map S1P gradients, and we have identified many of the key cells and enzymes that control these gradients. We are currently addressing how S1P gradients — and T cell residence time in tissues — are regulated during an immune response.
With this research, we hope to provide fundamental insight into how lipid gradients are shaped, and into how changing leukocyte residence times in tissues affects the immune response. We also hope that this work will translate to improved therapies for inflammatory disease. Drugs targeting S1P signaling are used clinically as immune suppressants. However, because S1P also regulates vascular stability and heart rate, side effects are a serious concern. By determining how S1P gradients are regulated, we may identify targets that enable spatially specific modulation of S1P signaling.
How does trafficking of acute lymphoblastic leukemia T cells differ from trafficking of normal T cells?
We are fascinated by how the migration of leukemia T cells differs from that of normal cells. Can these differences be targeted therapeutically? What do these differences reveal about how normal T cells move? We have found that loss of signaling through the chemokine receptor CXCR4 after disease onset decimates T cell acute lymphoblastic leukemia in both murine and human xenograft models of disease—an unexpected result given that CXCR4 plays relatively subtle roles in normal T cell development and peripheral T cell maintenance. Because CXCR4 antagonists are in clinical trials for other cancers, our results may quickly translate to an effective and relatively nontoxic therapy for this aggressive disease. We are currently trying to define additional trafficking requirements for T-ALL, particularly for metastasis to the central nervous system.