Cellular traffic through afferent lymphatic vessels

The lymphatic system has long been known to serve as a highway for migrating leukocytes from peripheral tissue to draining lymph nodes (dLNs) and back to circulation, thereby contributing to the induction of adaptive immunity and immunesurveillance. Lymphatic vessels (LVs) present in peripheral tissues upstream of a first dLN are generally referred to as afferent LVs. In contrast to migration through blood vessels (BVs), the detailed molecular and cellular requirements of cellular traffic through afferent LVs have only recently started to be unraveled. Progress in our ability to track the migration of lymph-borne cell populations, in combination with cutting-edge imaging technologies, nowadays allows the investigation and visualization of lymphatic migration of endogenous leukocytes, both at the population and at the single-cell level. These studies have revealed that leukocyte trafficking through afferent LVs generally follows a step-wise migration pattern, relying on the active interplay of numerous molecules. In this review, we will summarize and discuss current knowledge of cellular traffic through afferent LVs. We will first outline how the structure of the afferent LV network supports leukocyte migration and highlight important molecules involved in the migration of dendritic cells (DCs), T cells and neutrophils, i.e. the most prominent cell types trafficking through afferent LVs. Additionally, we will describe how tumor cells hijack the lymphatic system for their dissemination to draining LNs. Finally, we will summarize and discuss our current understanding of the functional significance as well as the therapeutic implications of cell traffic through afferent LVs.