A two-step model for Langerhans cell migration to skin-draining LN

Abstract

Although the role of Langerhans cells (LC) in skin immune responses is still a matter of debate, it is known that LC require the chemokine receptor CCR7 for migrating to skin-draining LN. A report in the current issue of the European Journal of Immunology unfolds some of the intricacies of LC migration, showing that LC need CXCR4, but not CCR7, for their migration from the epidermis to the dermis. Thus, LC migration to skin-draining LN occurs in two distinct phases: a first step from the epidermis to the dermis regulated by CXCR4 and a second CCR7-dependent step from the dermis to LN. Here we discuss the potential implications of this new two-step LC migration paradigm.

Figure 1

Two-step Langerhans cell migration to LN. Dermal DC (dDC, EpCAM⁻ and either Langerin⁺ or Langerin⁻) constitutively migrate to the LN in a process dependent on CCR7 and its ligands CCL19 and CCL21-leu (leucine isoform of CCL21), which are expressed by lymphatic endothelial cells. On the other hand, during steady-state non-inflammatory conditions, immature Langerhans cells (iLC, Langerin⁺EpCAM⁺) do not express CXCR4 or CCR7 and remain mostly restricted to the epidermal compartment (left panel). Upon exposure to inflammatory agents (e.g. haptens), iLC undergo maturation and upregulate CXCR4, whose ligand CXCL12 is also increased in the dermis during inflammation (right panel). CXCR4 expression allows maturing LC (mLC, Langerin⁺EpCAM⁺) to cross the dermo-epidermal junction and reach the dermis (first step). In the dermis, mLC acquire high levels of CCR7, endowing these cells with the capacity to migrate to skin-draining LN (second step). It is also possible that mLC functionally interact with dDC during their time in the dermis.