Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Abstract

Afferent lymphatic vessels (LVs) mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T cells. While DC migration is important for maintenance of tolerance and for induction of protective immunity, T cell migration through afferent LVs contributes to immune surveillance. In recent years, great progress has been made in elucidating the mechanisms of lymphatic migration. Specifically, time-lapse imaging has revealed that, upon entry into capillaries, both DCs and T cells are not simply flushed away with the lymph flow, but actively crawl and patrol and even interact with each other in this compartment. Detachment and passive transport to the dLN only takes place once the cells have reached the downstream, contracting collecting vessel segments. In this review, we describe how the anatomy of the lymphatic network supports leukocyte trafficking and provide updated knowledge regarding the cellular and molecular mechanisms responsible for lymphatic migration of DCs and T cells. In addition, we discuss the relevance of DC and T cell migration through afferent LVs and its presumed implications on immunity.

Keywords: T cell; afferent lymphatic vessel; dendritic cell; immunity; leukocyte; lymphatic endothelial cell; migration; trafficking.

Figure 1

Morphological and anatomical characteristics of afferent lymphatics. Afferent LVs begin as blind-ended initial capillaries in peripheral tissues. Lymphatic capillaries have a wide lumen and are surrounded by a thin and fenestrated basement membrane (BM). LECs in lymphatic capillaries (capLECs) have a characteristic oak-leaf shape and are attached to each other by discontinuous button-like junctions, thereby generating open flaps (primary valves). capLECs are connected to the interstitial extracellular matrix (ECM) via anchoring filaments, allowing the flaps to open when interstitial fluid pressure increases. This characteristic setup, together with the discontinuous BM render initial capillaries specialized structures for fluid uptake and leukocyte intravasation. Lymphatic capillaries subsequently merge into lymphatic collectors, which eventually connect to dLN. Contrary to capillaries, LECs in collectors (colLECs) are elongated in the direction of flow and are attached to each other by continuous zipper-like junctions. Collecting vessels are also surrounded by a thick and continuous BM and covered by a layer of lymphatic muscle cells (LMCs). This setup, together with the presence of intralymphatic valves, allows lymphatic collectors to periodically contract and expand, thereby generating flow and propagating lymph in the direction of the dLN. Efferent LVs exit from LNs and connect with subsequent LNs to eventually merge into the thoracic and right lymphatic ducts.

Figure 2

Schematic depiction of current in vivo and ex vivo or in vitro methods used to study leukocyte migration into and within afferent lymphatics. Detailed explanations and references to studies employing these methods are provided in the text of Section 4.

Figure 3

Leukocyte migration through afferent lymphatics occurs in a step-wise manner. (A) Summary of the key steps in DC and T cell migration from peripheral tissues through afferent LVs. (B) Description of the individual steps. Step 1: Interstitial migration: The interstitial space is comprised of fibroblasts and extracellular matrix (ECM) through which DC and T cells migrate in an ameboid fashion towards initial lymphatic capillaries. Step 2: Capillary entry: Attracted by the peri-lymphatic CCL21 chemokine gradient, DCs and T cells approach blind-ended capillaries and enter through specialized flaps formed by discontinuously joint capillary LECs (capLECs). Step 3: Intralymphatic crawling: DCs and T cells actively crawl and patrol within the capillary lumen, thereby interacting with the lymphatic endothelium. Step 4: Passive transport: migratory DCs and T cells eventually reach the downstream collecting vessels segments. Here, lymph flow increases due to vessel contractions mediated by the collector-surrounding lymphatic muscle cells (LMCs), leading to the detachment of leukocytes and their passive and rapid transport towards the dLN. X: Shortcut into afferent LVs: Under inflammatory conditions, DCs can additionally transmigrate and directly enter into lymphatic collectors [74].