Mechanisms and consequences of dendritic cell migration

Abstract

Dendritic cells (DCs) are critical for adaptive immunity and tolerance. Most DCs are strategically positioned as immune sentinels poised to respond to invading pathogens in tissues throughout the body. Differentiated DCs and their precursors also circulate in blood and can get rapidly recruited to sites of challenge. Within peripheral tissues, DCs collect antigenic material and then traffic to secondary lymphoid organs, where they communicate with lymphocytes to orchestrate adaptive immune responses. Hence, the migration and accurate positioning of DCs is indispensable for immune surveillance. Here, we review the molecular traffic signals that govern the migration of DCs throughout their life cycle.

Fig. 1

Programmatic outline of DC and DC precursor trafficking routes. DCs develop from precursors that originate from primary lymphoid tissues (PLT) such as the BM and the thymus. Precursors and committed DCs enter the circulation and seed peripheral tissues and SLOs (see also Figure 2 for an overview of the hematogenous route). From peripheral tissues, they can access afferent lymph upon receiving a mobilization signal and travel to the draining LN (see also Figure 3 for migration to the draining LN and Figure 4 for migration within the LN). Leukocytes leave LNs via the efferent lymph and are collected in the TD, which eventually guides DCs and their precursors back into the circulation. For individual migratory routes for specific DCs and their precursors refer to table 1.

Fig. 2

Hematogenous DC routes. This schematic outline illustrates various routes that DCs can take to and from the blood into various lymphoid and non-lymphoid tissues. DC precursors are released from the BM and enter the blood pool, which consists of: conventional DCs (or cDC), pDCs, and DC precursors (encompassing monocytes, HSPCs, and other committed DC precursors). Potential destinations of blood-borne DCs as well as the major trafficking molecules implicated in their migration are highlighted, including (from left to right) the skin, LN, thymus, and spleen, as well as their re-entry into the BM.

Fig. 3

DC trafficking in peripheral tissues. This schematic illustrates a proposed model for the interstitial migration for skin DCs from the cutaneous microenvironment to the afferent lymphatics en route to the LN. The migratory cascade is divided into five discrete steps (clockwise from top left), starting with recognition of a mobilizing signal (inset 1), detachment from structural tissue elements (inset 2), trafficking through interstitial space (inset 3), traversing the afferent lymphatic endothelium (inset 4), and transit through the afferent lymph vessels (inset 5). Major chemokine-chemokine receptor (CKRs) pathways and other trafficking molecules controlling DC migration are highlighted.

Fig. 4

DC networks and migratory pathways of DCs within the LN. This schematic depicts the DC network and anatomic features within the LN, including (clockwise from top left), the afferent lymphatics/LN entry point (inset 1), subcapsular sinus and the peri-follicular region (inset 2), the B cell follicle and T&B cell border (inset 3), the efferent lymphatics and LN exit point (inset 4), and the T cell zone/HEV (inset 5). Major structural features of the LN are depicted, in addition to T cells (grey circles), B cells (brown circles), and free flowing or processed Ag (black diamonds). The major trafficking pathways and chemotactic molecules guiding migratory and resident DC subsets within each zone are highlighted.