My research seeks answers to the question how circulating blood cells find their way in the body. Directed migration of blood-borne cells to distinct target tissues can be observed in embryos as soon as the circulatory system is established and plays a critical role throughout life in numerous physiologic and pathologic conditions. Despite considerable progress in this field, it is still beyond the reach of even the most sophisticated in vitro methodology to simulate the complex interplay of physical, cellular, biochemical, and other factors that determine blood cell behavior in microvessels. Therefore, we employ intravital microscopy to study the molecular mechanisms of interactions between blood cells and the vascular wall by direct observation in anesthetized mice. Using this approach, we have demonstrated that blood cell homing to most target tissues requires an initial tethering step that leads to rolling in postcapillary venules and is followed by an activation step which, in turn, triggers stationary adhesion and emigration. Each of these three steps (i.e. 1. rolling; 2. chemotactic stimulation; and 3. firm arrest) involves distinct molecular pathways whose unique combination is the reason why certain blood cells migrate to a particular organ, whereas others don't.
We are now dissecting the site-specific adhesion cascades that direct myeloid and lymphoid cells, hematopoietic stem cells and platelets to normal and diseased tissues. We have established models in mice that allow quantitative observations in Peyer's patches; gut; bladder; striated muscle; skin; pancreas; liver; knee joint; bone marrow; bone; and peripheral lymph nodes. The techniques for observing the latter three tissues were developed in my laboratory.
Understanding how lymphocytes, in particular T cells, home to and migrate within peripheral lymph nodes is a major focus of my group. To this end, we are using a panel of mice that are genetically deficient in specific adhesion pathways. We have also generated transgenic mouse strains that express fluorescent proteins in distinct T cell subsets. We are using these mice to study how T cells differentiate into effector and memory subsets; how this differentiation affects their migratory properties; and how antigen-presenting dendritic cells influence these processes. T cells and dendritic cells can be visualized in the intra- and extravascular space by intravital microscopy using both single- and multi-photon fluorescence techniques. This allows us to dissect the trafficking behavior of these immune cells at a resolution and specificity that could not be achieved with other methods.
Besides supervising and instructing the students and fellows in my laboratory (15-20 members), my current teaching activities include the co-direction and organization of the Immunology 201 and Immunology 202 semester courses for HMS graduate students. In addition, we have numerous collaborators in the Harvard community and elsewhere who perform intravital microscopy studies in our facility under my supervision. I also lecture regularly to HMS graduate students, postdoctoral fellows and staff about leukocyte adhesion, migration and homing.