Mechanisms of Lymphocyte Recirculation and Recruitment
In the mammalian immune system, cell migration plays an important role in the host defense against a variety of antigenic challenges. Cell migration is the process that delivers lymphocytes to virally infected tissues, organ allografts, or growing tumors. Understanding the mechanism of lymphocyte homing to the site of antigen challenge offers the potential for regulating this process clinically. For example, it would be desirable to enhance lymphocyte migration into virally infected tissues and malignant tumors, but suppress lymphocyte migration into organ allografts.In recent years, attempts to define the mechanism of lymphocyte homing to the site of inflammation have focused on cell adhesion molecules. These molecules are expressed on the cell surface and appear to regulate the interaction of lymphocytes with the endothelial cells that line the vessel wall. Our approach was to study the function of these molecules under physiologic conditions both in vitro and in vivo. Using a video microscopy chamber to simulate flow conditions in the inflammatory microcirculation, we studied the contribution of these cell adhesion molecules to lymphocyte movement, adhesion, and locomotion. The regulation of lymphocyte migration can be clarified by selectively inhibiting or augmenting the function of these cell adhesion molecules.Cell migration to the site of antigen challenge is a process that involves not only lymphocytes and endothelial cells, but complex microhemodynamic forces as well. The forces at the vessel wall appear to be important determinants of whether cells exit the microcirculation or remain in the flow stream. For example, during lymphocytic inflammation, microhemodynamic forces can vary widely as the microcirculation undergoes dramatic structural adaptation. It is possible that these structural changes facilitate lymphocyte transmigration. To study the effect of microhemodynamic forces on lymphocyte migration, we tracked migrating lymphocytes from the efferent lymph to the antigen-stimulated microcirculation. Using fluorescence and dark-field intravital video microscopy, we directly observed the movements of cells in the microcirculation. Defining the molecular and physiologic mechanisms of lymphocyte migration into the inflammatory tissue has led to new approaches to the inhibition and augmentation of cell migration in vivo.