Lymphatic system: an active pathway for immune protection

Abstract

Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which may include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases.

Keywords: Antigen delivery; Dendritic cell trafficking; Immune regulation; Lymph node; Lymphatic function.

Figure 1. Initial lymphatic vessels, collecting lymphatic vessels and the draining lymph node

A. Schematic figure of lymphatic system, including initial lymphatic vessels, collecting lymphatic vessel and the draining lymph node. Within the lymph node, fibroblastic reticular cells and high endothelial cells express CCL21 and CCL19 to attract T cells and dendritic cells at the paracortex area of lymph node. The lymph node conduit system, composed of collagen fibers, forms a scaffold to support lymph node architecture and facilitate quick fluid trafficking within the lymph node. B. Initial lymphatic vessel and collecting lymphatic vessel. The initial lymphatic vessels have oak-leaves shaped cell junctions (Button pattern). Collecting lymphatics have continuous junction molecules and basement membrane and organized smooth muscle cell coverage. Organized smooth muscle coverage in collecting lymphatics allows phasic lymphatic contractions to propel lymph through lymphatic vessels. C. The button shaped cell junction form lymphatic portals between lymphatic endothelial cells, which allows easy access of fluid and cells. Chemokine CCL21 expressed on lymphatic endothelial cell attract cells to lymphatic vessels and facilitate cell trans-lymphatic endothelial cell migration.

Figure 2. Lymph node conduit system

Multiphoton microscopy and 3D re-construction images of second harmonic generation, to reveal collagen distribution in lymph node. Collagen forms a dense capsule that surrounds LN and extends into LN to form LN conduit. The 3D side view shows the LN conduits extending from LN capsule. The 3D inside view shows in detail the LN conduits arising from LN capsule.

Figure 3. Lymph node macrophages

A. Schematic illustration of the lymph node macrophages. SSM: subcapsular sinus macrophage; MSM: medullary sinus macrophages. B. The close interaction between lymphatic endothelial cells and lymph node macrophages illustrated by immune fluorescent staining with Lyve-1 (Green) and CD169 (Red).